Posts Tagged ‘Unfolded protein response’

Protein folding

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

Series E. 2; 4.8

Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil.

The importance of protein folding

Joachim Pietzsch

Proteins are the biological workhorses that carry out vital functions in every cell. To carry out their task, proteins must fold into a complex three-dimensional structure, but what tells a protein which shape it should be and how does it achieve this?

Of all the molecules found in living organisms, proteins are the most important. They are used to support the skeleton, control senses, move muscles, digest food, defend against infections and process emotions. Proteins come in all shapes and sizes (Fig. 1)

  • they can be round (like haemoglobin), long (like collagen), strong (like spectrin c which protects erythrocytes (the cells that carry oxygen from the lungs to our tissues) from the powerful shearing forces they’re exposed to), or elastic (like titin, which controls muscle stretching and contraction). The name protein is derived from the Greek word prôtos, meaning – primary, or first rank of importance, and with good reason.

These are the most abundant component within a cell, more than half the dry weight of a cell is made up of proteins, and they have a range of indispensable roles; for example, enzymes, the biocatalysts that carry out crucial biochemical reactions in every cell that would otherwise be too slow to sustain life.

What is remarkable is that the more than 100,000 proteins in our bodies are produced from a set of only 20 building blocks, known as amino acids. All amino acids have the same basic structure, an amino group, a carboxyl group and a hydrogen atom, but differ due to the presence of a side-chain (known as R; (Fig. 2)). This side-chain varies dramatically between amino acids, from a simple hydrogen atom in the amino acid glycine to a complex structure found in tryptophan. Depending on the nature of the side-chain, an amino acid can be hydrophilic (water-attracting) or hydrophobic (water-repelling), acidic or basic; and it is this diversity in side-chain properties that gives each protein its specific character.

Creating a functional protein

The sequence of amino acids in a protein defines its primary structure. The blueprint for each amino acid is laid down by sets of three letters known as base triplets that are found in the coding regions of genes. These base triplets are recognized by ribosomes, the protein building sites of the cell, which create and successively join the amino acids together. This is a remarkably quick process: a protein of 300 amino acids will be made in little more than a minute.

The result is a linear chain of amino acids, but this only becomes a functional protein when it folds into its three-dimensional (tertiary structure) form. This occurs through an intermediate form, known as secondary structure, the most common of which are the rod-like a-helix and the plate-like b-pleated sheet (Fig. 3). These secondary structures are formed by a small number of amino acids that are close together, which then, in turn, interact, fold and coil to produce the tertiary structure that contains its functional regions (called domains).

Although it is possible to deduce the primary structure of a protein from a gene’s sequence, its tertiary structure cannot be determined (although it should become possible to make predictions when more tertiary sequences are submitted to databases). It can only be determined by complex experimental analyses and, at present, this information is only known for about 10% of proteins. It is therefore not yet known how an amino-acid chain folds into its tertiary structure in the short time scale (fractions of a second) that occurs in the cell. So, there is a huge gap in our knowledge of how we move from protein sequence to function in living organisms: the line of sight from the genetic blueprint for a protein to its biological function is blocked by the impenetrable jungle of protein folding, and some researchers believe that clearing this jungle is the most important task in biochemistry at present.

The quest to understand protein folding

One of the most important results in understanding the process of protein folding was a thought-provoking experiment that was carried out by Christian Anfinsen and colleagues in the early 1960s. They investigated a protein called ribonuclease, which they isolated from the pancreatic tissue of cattle. This enzyme, made up of 124 amino acids, cleaves any ribonucleic acid (RNA) that could be harmful to the cell, such as truncated RNA that would not make a fully operational protein. To do this, although this was not known in Anfinsen’s time, it briefly binds RNA in a binding site and requires several sulphur-containing amino-acid cysteine residues in the protein, which form bonds with each other (called disulphide bridges) and hold the protein structure together.

Ribonuclease can be denatured by adding certain chemicals or by heat. The disulphide bridges break and other forces of attraction between amino acids disappear, which makes the enzyme collapse into a tangled, useless ball. In various studies, Anfinsen showed that this denaturation process could be completely reversed by removing these denaturing chemicals or by lowering the temperature. The ribonuclease then folds back to its natural functional state on its own. So, Anfinsen concluded that the amino-acid sequence determines the shape of a protein, a finding for which Anfinsen received the Nobel Prize in Chemistry in 1972.

But, if this is true, how do proteins find the right conformation out of the simply endless number of potential three-dimensional forms that it could randomly fold into? After all, the folding of a protein is not a chemical reaction, with a bond breaking here and a new one forming there. It is more like the weaving of an intertwined molecular pattern, the stability of which is defined by innumerable forces between atoms. Indeed, Cyrus Levinthal calculated in 1969 that finding the strongest attraction by simple trial and error would be impossible. He said that even if a protein only consisted of 100 amino acids and each of these flexible residues could only take on two different spatial orientations, the protein could theoretically adopt as many as 1030 possible conformations. Assuming a protein could try out 100 billion different conformations per second, it would still take 100 billion years to try all possibilities. So, Levinthal suggested that nature must have devised more effective methods to achieve this and postulated the existence of defined sets of folding pathways by which protein folding can take place rapidly.

However, we now know that such fixed protein folding pathways do not seem to exist. Various protein folding pathways that have been investigated experimentally and theoretically in recent years have thrown up interesting hypotheses, but have remained hard to prove in working models. In the case of proteins of less than 100 amino acids, only two levels of folding can be observed, the unfolded protein (which occurs in numerous forms) and the finished, folded, functional protein. For larger proteins, three steps can be observed. The intermediate is either a so-called molten globule, which is formed by a process called hydrophobic collapse (in which all hydrophobic side-chains suddenly slide inside the protein or clump together) or a structure in which the secondary structures of the protein are already fully formed. However, there is disagreement about whether these intermediates are formed en route to the correct folding pattern, or whether they represent structural cul-de-sacs.

Finding the energy to fold

As with all processes in nature, protein folding also needs energy, the process has to obey the laws of thermodynamics. A protein always folds so that it achieves the lowest possible energy, just as we always try to adopt the most comfortable position, in which we need to move about least, when going to sleep. It is thought that this is achieved by using an energy gradient or funnel along the path from the random tangle to the folded protein. Alan Fersht of Cambridge University used the following analogy to illustrate this model: if you blindfold a golfer and let him hit the ball in any direction he likes, the probability that he will hole the ball is almost infinitesimal. The same is true of a protein finding the right form by chance. However, if all parts of the golf course slope toward the hole, which is at the lowest point in the area, even a blindfolded golfer has a good chance of finding the hole. So, fixed reaction pathways are not necessary, as each protein seeks out its natural shape through a funnel of declining energy; it can take many folding routes and still reach its target of the completed tertiary structure.

A helping hand

This understanding of protein folding was obtained from computer models (in silico) or from experiments in the laboratory (in vitro) in which an individual protein was denatured to observe it folding back into its original form. But, the situation is considerably more complex in the living cell (in vivo). Although the fundamental energy rules also apply here, folding at least of large proteins rarely takes place spontaneously, as the ribosomes do not synthesize only one protein at a time. Instead, cells contain a vast number of proteins and other biomolecules at the extraordinarily high concentration of 340 grams per litre. Ordered protein folding in this cramped chaos is only possible under the supervision of specialized molecules, called chaperones, which accompany proteins and make sure that those that are being formed at the ribosomes do not clump together prematurely (Fig. 4). Chaperones do not merely oversee the folding of the protein, they also protect its tertiary structure in situations in which the cell is under stress; for example, elevated body temperature, so these chaperones have also been classified as heat-shock proteins (HSPs).

The HSP70s, so called because they have a molecular weight of 70 kilodaltons, are the most important class of chaperones. They bind to the developing protein chain and protect those parts of the newly formed protein that are particularly sensitive to premature reaction with the environment and therefore to malformation. When they let go of the new protein chain it is ready to fold. It is now taken over by a chaperonin, a molecule shaped like a double ring, which fits round the protein chain like a cylinder so that it can fold undisturbed inside (Fig. 4). Although the cylindrical folding cage opens every ~10 seconds, the protein only leaves the chaperonin when it has achieved its required form.

We now understand better than ever how protein folding, both in vitro and in vivo, takes place. And this, in turn, has given us a better understanding of the origin and course of diseases that are associated with defective protein folding. But why the normal folding of every protein always runs towards a predetermined goal and what this goal looks like, that is, what the instructions in the primary structure are that determine the correct tertiary structure is still a great mystery, even though the number of proposed models has dramatically increased. Computer simulations cannot yet solve the folding code that is hidden in the primary structure by simply calculating the molecular dynamics atom by atom, as to work through just 50 milliseconds of folding would take even the fastest computer around 30,000 years. Any realistic hope of cracking the folding code, such as to produce special designer proteins that evolution had not planned, is probably a very long way off. However, our improved understanding of the route that a protein must take from its synthesis to the correct folded form already enables us to contemplate better treatments or even cures for diseases in which proteins have departed from the correct folding route (see Treating protein folding diseases).

The Anfinsen Experiment in Protein Folding


Chaperones, which help proteins find their native, active conformation

Kazutoshi Mori and Peter Walter

PNAS 2014; 111(50): 17696–17697 http://dx.doi.org:/10.1073/pnas.1419343111

Kazutoshi Mori and Peter Walter

Albert Lasker
Basic Medical Research Award

For discoveries concerning the unfolded protein response — an intracellular quality control system that detects harmful misfolded proteins in the endoplasmic reticulum and signals the nucleus to carry out corrective measures.


Proteins that are secreted from the cell or inserted into the plasma membrane, transit through the endoplasmic reticulum where they are properly folded and assembled and may undergo post-translational modification. Walter tells the story of the exciting discovery made in his lab of the “unfolded protein response”, a feedback pathway that ensures that the cell makes enough ER to properly modify all the secreted proteins in the cell.


Kazutoshi Mori and Peter Walter
For discoveries concerning the unfolded protein response — an intracellular quality control system that detects harmful misfolded proteins in the endoplasmic reticulum and signals the nucleus to carry out corrective measures.

The 2014 Albert Lasker Basic Medical Research Award honors two scientists for their discoveries concerning the unfolded protein response, an intracellular quality-control system that detects harmful misfolded proteins in the endoplasmic reticulum and signals the nucleus to carry out corrective measures. Kazutoshi Mori (Kyoto University) and Peter Walter (University of California, San Francisco) identified core components of this process and unveiled unexpected aspects of its mechanism.

Approximately one third of cellular proteins pass through the endoplasmic reticulum (ER), a netlike labyrinth of membrane-bound tubes and flattened sacs inside the cell. Work in the 1960s revealed that the ER sorts and transports proteins that are destined for export or the cell’s surface, and we now know that the ER allows cargo to pass only after applying stringent standards. In particular, proteins must assume correct three-dimensional shapes to perform their jobs, and the ER fosters this outcome. Furthermore, when unfolded proteins accumulate in this compartment, the cell bolsters the ER’s folding capacity. This phenomenon forms the linchpin of the unfolded protein response (UPR).

The first clues about this system’s existence emerged in the late 1970s, when researchers discovered that glucose starvation drives cells to boost production of particular proteins. Amy Lee (University of Southern California) reported in 1983 that the rise stems from an increase in the quantity of messenger RNA (mRNA) templates for these glucose-regulated proteins, or GRPs.

Three years later, Hugh Pelham (Medical Research Council, Cambridge) established that one of the GRPs, GRP78, resides in the ER and resembles a protein that prevents heat-damaged proteins from clumping. When glucose supplies drop, sugars that normally decorate some proteins are no longer available. Pelham proposed that the resulting sugar-deficient proteins stick together, perhaps because they misfold, and that GRP78, like its molecular relative, thwarts protein aggregation. Pelham also found that GRP78 was identical to another protein, BiP, that associates with partially assembled antibody molecules in the ER. In parallel, Mary-Jane Gething and Joseph Sambrook (University of Texas Southwestern Medical Center) showed that BiP attaches to misfolded forms of a different protein in the ER.

These findings hinted that BiP helps proteins fold; if true, manufacture of BiP in response to unfolded proteins would serve a clear benefit. The connection between glucose starvation and folding remained murky, however, and the model relied on that link. In 1988, Gething and Sambrook established that misfolded protein rather than sugar-adornment defects sends the alert to ramp up BiP output.

In 1989, yeast BiP surfaced. Its quantities also climb in response to unfolded ER proteins. Mori joined Gething and Sambrook’s lab as a postdoctoral fellow, and the group identified a short series of DNA letters that abuts the BiP gene. This sequence spurs molecular machinery to copy, or transcribe, the BiP DNA into mRNA when unfolded proteins accumulate in the ER; the sequence, when placed next to a different gene, similarly turns on its transcription.

Together, these observations suggested that cells must somehow monitor the abundance of unfolded proteins in the ER and transmit that information to the nucleus, which houses the genes. These events spark production of BiP and other proteins that promote folding, which reverse the problem. But no one knew how the nuclear equipment senses the ER environment.

The complexity of Ire1
Independently, Mori, in Texas, and Walter, in San Francisco, placed the DNA stretch that Mori had uncovered next to a gene whose product makes a blue substance. When unfolded proteins accumulate in the ER and the engineered yeast cells send the usual signal to the nucleus, it stimulates not only typical UPR targets, but also the gene that turns the yeast blue. Yeast with defects in the UPR system would not change color, the researchers reasoned.

In 1993, the investigators used this scheme to isolate white yeast strains and thus tracked down the faulty genes whose normal versions presumably contribute to the UPR. One encodes a protein called Ire1.

Sequence analysis of Ire1 suggested that it is a kinase—an enzyme that adds phosphates to itself and/or other proteins. Additional work by Walter and Mori confirmed and extended this prediction. They found that Ire1 lies in the ER membrane with its kinase portion in the cytoplasm. In this orientation, the ER region could detect an unfolded protein signal and the other end could convey the message to cytoplasmic partners.

Mammalian kinases were well known to monitor environmental cues and, by adding phosphates to themselves or other molecules, trigger adaptive physiological changes. Perhaps, Mori and Walter reasoned, Ire1 would behave similarly.

To figure out how Ire1 delivers the unfolded-protein message, Walter and Mori (by then an independent investigator in Japan) set out to identify the presumptive courier that picks up the signal and carries it to the nucleus. They sought a protein that binds to the DNA sequences adjacent to UPR target genes and provokes transcription. The investigators captured the component they sought, a protein that previously had been named Hac1.

Their results, reported in 1996, contradicted expectation. In the simplest scenario, the theoretical protein to which Ire1 affixes a phosphate would be ready for action upon stimulation. Hac1, however, is not ready for anything; rather, it is manufactured only after the UPR alarm rings.

A crucial clue to explain this result came from the observation that the Hac1-encoding mRNA shrinks when unfolded proteins accumulate. Instead of adding a phosphate to another protein, Ire1 prompts removal of a chunk of Hac1’s mRNA. Additional work by Walter, which was confirmed and extended by Mori, established thatHAC1 precursor mRNA contains an internal stretch of 252 genetic letters that is eliminated to supply the blueprint for active Hac1.

A canonical molecular machine splices sequences from precursor mRNAs and operates in the nucleus. The plot thickened when Walter showed that this apparatus does not act on HAC1 mRNA. Instead, he found, the severed HAC1 mRNA is stitched together by a cytoplasmic enzyme—tRNA ligase—that normally joins the two components of a different type of RNA, transfer RNA.

The search was now on for an enzyme that excises the middle piece of the HAC1 precursor mRNA. Inspired by a related protein’s behavior, Walter showed that the cytoplasmic segment of Ire1, which contains the kinase and an additional stretch of protein, could cut HAC1 precursor mRNA at the expected sites. Then he demonstrated that the splicing reaction could occur in the test tube with only two enzymes: Ire1 cleaves the HAC1 precursor mRNA at both splice junctions, and the transfer RNA ligase sews them together.

Mammalian systems unfold
As these details of the yeast UPR were materializing, researchers were struggling to gain traction in the mammalian system. In 1998, Mori unearthed a sequence that was common only to genes that fire up in response to unfolded ER proteins. This element rouses several UPR target genes, he found. Furthermore, a human protein called ATF6 binds to this DNA motif and activates adjacent genes.

Mori noticed that an overabundance of unfolded proteins incites conversion of full-length ATF6 to a smaller version; the large form dwells in the ER, whereas the trimmed one resides in the nucleus. This and other work suggested that excess unfolded proteins trigger release of a portion of ER membrane-bound ATF6. The liberated fragment travels to the nucleus and activates transcription of UPR target genes.

While Mori was discovering and elucidating ATF6’s role in the UPR, David Ron (New York University School of Medicine) and Randal Kaufman (University of Michigan Medical Center) found mammalian versions of Ire1, which share fundamental functional features with their yeast cousin. Three years later, Mori and Ron identified the human and worm versions of yeast Hac1, a protein known as XBP1.

In the meantime, near the beginning of 1999, David Ron and Ron Wek (Indiana University School of Medicine) had independently uncovered a third arm of the UPR, which depends on a protein called PERK. Like Ire1 and ATF6, PERK also lies across the ER membrane. Furthermore, its ER domain resembles that of Ire1. On the cytoplasmic side, a protein kinase segment of PERK adds phosphates to a particular protein, which then impedes translation of mRNAs. As a result, fewer proteins enter the ER, thus lightening the folding load.

Strength in numbers
In the last ten years, Walter, with UCSF colleague Robert Stroud, has peered more closely at Ire1 activation with X-ray crystallography. Previous work by Mori, Walter, and others had suggested that UPR induction causes Ire1 molecules to snuggle up in the membrane. By studying yeast Ire1, Walter and Stroud provided an atomic-level rationale for those results and illuminated details of the reaction.

In addition to providing assistance during protein folding, BiP attaches to Ire1 on the side that lies within the ER; when BiP falls off, naked Ire1 molecules pair up and create grooves that bind the unfolded proteins, Walter and Stroud suggest. Multiple Ire1 duos then congregate to form higher order structures; such association rearranges their cytoplasmic segments, positioning them so they can grab and then snip the HAC1/XBP1 mRNA, according to the model.

Researchers are still uncovering layers in the UPR. For example, Ire1 governs ER membrane synthesis and a system that shuttles recalcitrant unfolded proteins from the ER to a cellular incinerator. Even with these additional components, the unfolded protein burden sometimes surpasses the cell’s management capacity. That situation can trigger cell suicide, which obliterates unhealthy cells that might otherwise wreak havoc. Investigators are deciphering how the Ire1, ATF6, and PERK branches of the pathway help cells make life-and-death decisions.

Many scientists are now pursuing ways to harness the UPR for medical advantage. Certain forms of some inherited diseases that cause elevated cholesterol levels, cystic fibrosis, and retinitis pigmentosa produce abnormal proteins that do not fold properly and overwhelm the UPR.

Walter and Mori have unraveled a process with numerous unusual features. Their work has unlocked a multi-layered, highly choreographed system that lies at the heart of normal cellular function.

by Evelyn Strauss



Peter Walter: Winner of the 2015 Vilcek Prize in Biomedical Science


Kazutoshi Mori of Kyoto University in Japan and Peter Walter of the University of California, San Francisco, have won the 2014 Lasker Award for basic medical research. Mori and Walter are being honored by the Albert and Mary Lasker Foundation for their work related to the unfolded protein response—a cellular stress response that has been implicated in several protein-folding diseases.

In its announcement, the foundation said that “Mori and Walter’s work has led to a better understanding of inherited diseases such as cystic fibrosis, retinitis pigmentosa, and certain elevated cholesterol conditions in which unfolded proteins overwhelm the unfolded protein response.”

Three years ago, the Lasker Foundation honored Franz-Ulrich Hartl and Arthur Horwich for their protein-folding work with its 2011 basic research award.

Meanwhile, Alim Louis Benabid of Joseph Fourier University in Grenoble, France, and Mahlon DeLong of the Emory University School of Medicine in Atlanta, Georgia, have won the this year’s Lasker-DeBakey Clinical Medical Research Award for their deep-brain stimulation work that has been used to help restore and motor function in patients with advanced Parkinson’s disease.

And the University of Washington’s Mary-Claire King has won the 2014 Lasker-Koshland Special Achievement Award in Medical Science for “bold, imaginative, and diverse contributions to medical science and human rights” related to her work to reunite missing persons or their remains with their families, as well as her discovery of the cancer-related BRCA1 gene locus. In a commentary published in JAMA today (September 8), King and her colleagues advocated for population-based screening for cancer-related genetic variants. “Population-wide screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine,” they wrote.

This year’s recipients will receive a $250,000 honorarium per category. The awards will be presented on Friday, September 19, in New York City.


2014Life Science and MedicineProfessor Kazutoshi Mori and Professor Peter Walter



World’s Largest Protein Interaction Map Created

GEN News  Sep 8, 2015

A veritable tree-of-life investigation shows how proteins fit together and interact. [iStock/xrender]


An international research team reports that it has studied cells from numerous organisms, from amebae to worms to mice to humans, to show how proteins fit together to build different tissues and bodies. They say they uncovered tens of thousands of new protein interactions, accounting for about a quarter of all estimated protein contacts in a cell.

When even a single one of these interactions is lost it can lead to disease, and the map is already helping scientists spot individual proteins that could be at the root of complex human disorders, the team points out in an article (“Panorama of ancient metazoan macromolecular complexes”) in Nature. They add that their data will be available through open access databases.

Proteins work in teams by sticking to each other to carry out their jobs. Many proteins come together to form so called molecular machines that play key roles, such a building new proteins or recycling those no longer needed by literally grinding them into reusable parts. But for the vast majority of proteins, and there are tens of thousands of them in human cells, we still don’t know what they do.

This is where the map created by researchers led by Andrew Emili, Ph.D., from the University of Toronto’s Donnelly Centre and Edward Marcotte, Ph.D., from the University of Texas at Austin map comes in. Using a technique developed by the groups, the scientists were able to fish thousands of protein machineries out of cells and count individual proteins they are made of. They then built a network that, similar to social networks, offers clues into protein function based on which other proteins they hang out with. For example, a new and unstudied protein, whose role we don’t yet know, is likely to be involved in fixing damage in a cell if it sticks to cell’s known “handymen” proteins.

The study gathered information on protein machineries from nine species that represent the tree of life: baker’s yeast, amebae, sea anemones, flies, worms, sea urchins, frogs, mice, and humans. The new map expands the number of known protein associations over 10-fold, and gives insights into how they evolved over time.

“For me the highlight of the study is its sheer scale. We have tripled the number of protein interactions for every species. So across all the animals, we can now predict, with high confidence, more than 1 million protein interactions [which is] a fundamentally ‘big step’ moving the goal posts forward in terms of protein interactions networks,” says Dr. Emili, who is also Ontario Research Chair in Biomarkers in Disease Management and a professor in the department of molecular genetics.

The researchers discovered that tens of thousands of protein associations remained unchanged since the first ancestral cell appeared, one billion years ago, preceding all of animal life on Earth.

“Protein assemblies in humans were often identical to those in other species. This not only reinforces what we already know about our common evolutionary ancestry, it also has practical implications, providing the ability to study the genetic basis for a wide variety of diseases and how they present in different species,” says Dr. Marcotte, who notes that the map is already proving useful in pinpointing possible causes of human disease.

One example is a newly discovered molecular machine, dubbed Commander, which consists of about a dozen individual proteins. Genes that encode some of Commander’s components had previously been found to be mutated in people with intellectual disabilities but it was not clear how these proteins worked.

Because Commander is present in all animal cells, the scientists went on to disrupt its components in tadpoles, revealing abnormalities in the way brain cells are positioned during embryo development and providing a possible origin for a complex human condition.

“With tens of thousands of other new protein interactions, our map promises to open many more lines of research into links between proteins and disease, which we are keen to explore in depth over the coming years,” says Dr. Emili.

Hormone Injections May Have Spread ‘Seeds’ of Alzheimer’s

by Seth Augenstein


The “seeds” of Alzheimer’s and related brain diseases may be transmitted by direct tissue transplantation, according to a new study.

The brains of eight people showed development of Creutzfeldt-Jakob disease, caused by treatments with contaminated growth hormones from human cadavers decades before, said the scientists, who published their findings in this week’sNature. Six of the eight also had the amyloid buildup that is a tell-tale sign of Alzheimer’s.

“This is the first evidence of real-world transmission of amyloid pathology,” John Hardy, a University College London molecular neuroscientist, reportedly told the journal.

The hormone treatments were administered to people who were short in height. The samples were taken from cadavers’ pituitary glands that contaminated with prions. The treatments started in 1958, and were halted in 1985 due to reports of Creutzfeldt-Jakob. By the year 2000, 38 of the patients had developed the disease. By 2012, the number had grown to 450 cases among the recipients of the cadaver-derived HGH and some other medical procedures, like transplants and brain surgery.

The study last week showed that the newly-understood Multiple System Atrophy could be spread by direct contact with re-used surgical instruments.

“You can’t kill a protein, and it can stick tightly to stainless steel, even when the surgical instrument is cleaned,” said Kurt Giles, a UCSF researcher and one of the authors of that MSA study.

Brain-eating cannibals from Papua New Guinea were the subject of a June study analyzing their genetic adaptations allowing them to survive a prion disease called kuru. The authors of the newest paper on the hormone spread of Creutzfeldt-Jakob were also cautious in pointing out particular dangers. 

Researchers Uncover More About The Elusive Pericyte-Tumour Interaction.

Sept 11, 2015     by Healthinnovations       Reported by Aviva Lev-Avi, PhD, RN

Tumours are known to evade the immune system by a variety of mechanisms, one of which is the recruitment of ‘myeloid-derived suppressor cells’ (MDSC). MDSCs suppress the ability of the immune system’s killer T-cells to destroy cancer cells. It is known that the more MDSCs present, the worse the prognosis or therapy response of the patient. Tumours secrete signal molecules such as interleukin-6 (IL-6) that help in recruiting MDSCs, however; the mechanisms behind IL-6 tumour secretion are quite unknown.

Now, a study from researchers at Karolinska Institutet is the first to suggest that cells in the tumour blood vessels contribute to a local environment that protects the cancer cells from these tumour-killing immune cells. The team state that their study can contribute to the development of better immune-based cancer therapies.  The study is published in the Journal of the National Cancer Institute.

Chemists solve major piece of cellular mystery

08/28/2015 Kimm Fesenmaier, California Institute of Technology


Not just anything is allowed to enter the nucleus, the heart of eukaryotic cells where, among other things, genetic information is stored. A double membrane, called the nuclear envelope, serves as a wall, protecting the contents of the nucleus.

The NPC is targeted by a number of diseases, including some aggressive forms of leukemia and nervous system disorders such as a hereditary form of Lou Gehrig’s disease. Now a team led by André Hoelz, assistant professor of biochemistry at Caltech, has solved a crucial piece of the puzzle.

Hoelz and his colleagues published a paper describing the atomic structure of the NPC’s coat nucleoporin complex, a subcomplex that forms what they now call the outer rings. The team has now solved the architecture of the pore’s inner ring, a subcomplex that is central to the NPC’s ability to serve as a barrier and transport facilitator. They built up the complex and then systematically dissected it. Then they validated how it works in vivo, in a species of fungus.

“Using an interdisciplinary approach, we solved the architecture of this subcomplex and showed that it cannot change shape significantly,” says Hoelz. “It is a relatively rigid scaffold that is incorporated into the pore and basically just sits as a decoration, like pom-poms on a bicycle. It cannot dilate.”


Folding Funnels Reveal Protein’s Inner Life

Tue, 03/22/2016 – 12:17pm
Rick Kubetz, University of Illinois at Urbana-Champaign
The molecular folding funnel contains all of the stable molecular states and folding pathways between them, providing important information about structure and mechanisms that can reveal how a polymer or protein folds, or aid in the design of drug molecule or ligands with a particular shape.
The molecular folding funnel contains all of the stable molecular states and folding pathways between them, providing important information about structure and mechanisms that can reveal how a polymer or protein folds, or aid in the design of drug molecule or ligands with a particular shape.

Proteins are the molecules of life. They are chemically programmed by their amino acid sequence to fold into highly organized conformations that underpin all of biological structure (e.g., hair, scales) and function (e.g., enzymes, antibodies). Understanding the sequence-structure-function relationship—the “protein folding problem”—is one of the great, unsolved problems in physical chemistry, and is of inestimable scientific value in exposing the inner workings of life and the rational design of molecular machines.

“This work lays the foundations to recover the protein folding landscapes directly from experimental data, providing a route to new understanding and rational design of proteins,” explained Andrew Ferguson, an assistant professor of materials science and engineering at the University of Illinois at Urbana-Champaign. “While we remain far from this goal, our understanding of protein folding was revolutionized by the ‘new view’ that envisages molecular folding as a conformational search over a funneled free energy surface.”

According to Ferguson, the single-molecule free energy surface encodes all of the thermodynamics and pathways of folding, dictating protein structure and dynamics. Each point on the landscape corresponds to an ensemble of similar protein conformations, and the height of the landscape prescribes their stability. It is a key goal of physical chemistry to determine molecular folding landscapes.

“Molecular folding landscapes can be inferred from long computer simulations in which the positions of all atoms in the molecule are known,” said Jiang Wang, a graduate research assistant and first author of the paper, “Nonlinear reconstruction of single-molecule free energy surfaces from univariate time series,” published in the March 21, 2016 issue of Physical Review E.

“Experimental techniques such as single molecule Förster resonance energy transfer (FRET) can measure distances between covalently-grafted fluorescent dye molecules to track the size of the molecule as a function of time, but it has so far not been possible to reconstruct folding funnels from experimental measurements of single coarse-grained observables,” Ferguson explained. “In this work, we have integrated nonlinear machine learning and statistical thermodynamics with Takens’ Theorem from dynamical systems theory to demonstrate in computer simulations of a hydrophobic polymer chain that it is possible to determine molecular folding landscapes from time series of a single experimentally-accessible observable.”

“The information loss associated with its reconstruction from a single observable means that the topography of the reconstructed funnel may be perturbed—the heights and depths of the free energy peaks and valleys may be altered—but it faithfully preserves the topology of the true funnel—the locality, continuity, and connectivity of molecular configurations,” Wang noted. “This means that the folding funnel determined from measurements of, in this case, the head-to-tail distance of the chain is geometrically and topologically identical and contains precisely the same molecular states and transition pathways as that computed from knowledge of all the atomic positions,” Ferguson added.

“We are very excited by this idealized proof of principle for computer simulations of a polymer chain, and are currently working to extend our analyses to simulations of biologically realistic peptides and proteins, and partner with single molecule biophysicists to apply our technique to experimental measurements of real proteins,” Ferguson said.


Nonlinear reconstruction of single-molecule free-energy surfaces from univariate time series

Jiang Wang and Andrew L. Ferguson
Phys. Rev. E 93, 032412 – Published 21 March 2016     http://dx.doi.org/10.1103/PhysRevE.93.032412
The stable conformations and dynamical fluctuations of polymers and macromolecules are governed by the underlying single-molecule free energy surface. By integrating ideas from dynamical systems theory with nonlinear manifold learning, we have recovered single-molecule free energy surfaces from univariate time series in a single coarse-grained system observable. Using Takens’ Delay Embedding Theorem, we expand the univariate time series into a high dimensional space in which the dynamics are equivalent to those of the molecular motions in real space. We then apply the diffusion map nonlinear manifold learning algorithm to extract a low-dimensional representation of the free energy surface that is diffeomorphic to that computed from a complete knowledge of all system degrees of freedom. We validate our approach in molecular dynamics simulations of a C24H50 n-alkane chain to demonstrate that the two-dimensional free energy surface extracted from the atomistic simulation trajectory is – subject to spatial and temporal symmetries – geometrically and topologically equivalent to that recovered from a knowledge of only the head-to-tail distance of the chain. Our approach lays the foundations to extract empirical single-molecule free energy surfaces directly from experimental measurements.

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Liver Endoplasmic Reticulum Stress and Hepatosteatosis

Larry H Bernstein, MD, FCAP


1. Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice.

Fuchs CD, Claudel T, Kumari P, Haemmerle G, et al.
LabExpMol Hepatology, Medical Univ of Graz, Austria.
Hepatology. 2012 Jul;56(1):270-80.   http://dx.doi.org/10.1002/hep.25601. Epub 2012 May 29.

Nonalcoholic fatty liver disease (NAFLD) is characterized by

  • triglyceride (TG) accumulation and
  • endoplasmic reticulum (ER) stress.

Fatty acids (FAs) may trigger ER stress, therefore,

  •  the absence of adipose triglyceride lipase (ATGL/PNPLA2)-
    • the main enzyme for intracellular lipolysis,
  • releasing FAs, and
  • closest homolog to adiponutrin (PNPLA3)

recently implicated in the pathogenesis of NAFLD-

  • could protect against hepatic ER stress.

Wild-type (WT) and ATGL knockout (KO) mice

  •  were challenged with tunicamycin (TM) to induce ER stress.

Markers of hepatic

  •  lipid metabolism,
  • ER stress, and
  • inflammation were explored
    • for gene expression by
    •  serum biochemistry,
    • hepatic TG and FA profiles,
    • liver histology,
    • cell-culture experiments were performed in Hepa1.6 cells
  • after the knockdown of ATGL before FA and TM treatment.

TM increased hepatic TG accumulation in ATGL KO, but not in WT mice. Lipogenesis and β-oxidation
were repressed at the gene-expression level
(sterol regulatory element-binding transcription factor 1c,
fatty acid synthase, acetyl coenzyme A carboxylase 2, and carnitine palmitoyltransferase 1 alpha) in
both WT and ATGL KO mice. Genes for very-low-density lipoprotein (VLDL) synthesis (microsomal
triglyceride transfer protein and apolipoprotein B)

  •  were down-regulated by TM in WT
  • and even more in ATGL KO mice,
  • which displayed strongly reduced serum VLDL cholesterol levels.

ER stress markers were induced exclusively in TM-treated WT, but not ATGL KO, mice:

  •  glucose-regulated protein,
  • C/EBP homolog protein,
  • spliced X-box-binding protein,
  • endoplasmic-reticulum-localized DnaJ homolog 4, and
  • inflammatory markers Tnfα and iNos.

Total hepatic FA profiling revealed a higher palmitic acid/oleic acid (PA/OA) ratio in WT mice.
Phosphoinositide-3-kinase inhibitor-

  • known to be involved in FA-derived ER stress and
  • blocked by OA-
  • was increased in TM-treated WT mice only.

In line with this, in vitro OA protected hepatocytes from TM-induced ER stress. Lack of ATGL may protect from
hepatic ER stress through alterations in FA composition. ATGL could constitute a new therapeutic strategy
to target ER stress in NAFLD.
PMID: 22271167 Diabetes Obes Metab. 2010 Oct;12 Suppl 2:83-92.

2. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.
Ferré P, Foufelle F. INSERM, and Université Pierre et Marie Curie-Paris, Paris, France.    PMID: 21029304

Excessive availability of plasma fatty acids and lipid synthesis from glucose (lipogenesis) are important determinants of steatosis.
Lipogenesis is an insulin- and glucose-dependent process that is under the control of specific transcription factors,

Insulin induces the maturation of SREBP-1c in the endoplasmic reticulum (ER).

  • SREBP-1c in turn activates glycolytic gene expression,
    • allowing glucose metabolism, and
    • lipogenic genes in conjunction with ChREBP.

Lipogenesis activation in the liver of obese markedly insulin-resistant steatotic rodents is then paradoxical.
It appears the activation of SREBP-1c and thus of lipogenesis is

  •  secondary in the steatotic liver to an ER stress.

The ER stress activates the

  •  cleavage of SREBP-1c independent of insulin,
  • explaining the paradoxical stimulation of lipogenesis
  • in an insulin-resistant liver.

Inhibition of the ER stress in obese rodents

  •  decreases SREBP-1c activation and lipogenesis and
  • improves markedly hepatic steatosis and insulin sensitivity.
  • ER is thus worth considering as a potential therapeutic target for steatosis and metabolic syndrome.

3. SREBP-1c transcription factor and lipid homeostasis: clinical perspective
Ferré P, Foufelle F
Inserm, Centre de Recherches Biomédicales des Cordeliers, Paris, France.
Horm Res. 2007;68(2):72-82. Epub 2007 Mar 5. PMID:17344645

Insulin has long-term effects on glucose and lipid metabolism through its control on the expression of specific genes.
In insulin sensitive tissues and particularly in the liver,

  •  the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) transduces the insulin signal, which is
  • synthetized as a precursor in the membranes of the endoplasmic reticulum
  • which requires post-translational modification to yield its transcriptionally active nuclear form.

Insulin activates the transcription and the proteolytic maturation of SREBP-1c, which induces the

  •  expression of a family of genes
  • involved in glucose utilization and fatty acid synthesis and
  • can be considered as a thrifty gene.

Since a high lipid availability is

  •  deleterious for insulin sensitivity and secretion,
  • a role for SREBP-1c in dyslipidaemia and type 2 diabetes
  • has been considered in genetic studies.

SREBP-1c could also participate in

  •  hepatic steatosis observed in humans
  • related to alcohol consumption and
  • hyperhomocysteinemia
  • concomitant with a ER-stress and
  • insulin-independent SREBP-1c activation.

4. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c
Ferré P, Foufelle F
INSERM, Centre de Recherches des Cordeliers and Université Pierre et Marie Curie-Paris, Paris, France.
Diabetes Obes Metab. 2010 Oct;12 Suppl 2:83-92. PMID: 21029304

Lipogenesis in liver steatosis is

  •  an insulin- and glucose-dependent process
  • under the control of specific transcription factors,
  • sterol regulatory element binding protein 1c (SREBP-1c),
  • activated by insulin and carbohydrate response element binding protein (ChREBP)

Insulin induces the maturation of SREBP-1c in the endoplasmic reticulum (ER).
SREBP-1c in turn activates glycolytic gene expression, allowing –

  •  glucose metabolism in conjunction with ChREBP.

activation of SREBP-1c and lipogenesis is secondary in the steatotic liver to ER stress, which

  •  activates the cleavage of SREBP-1c independent of insulin,
  • explaining the stimulation of lipogenesis in an insulin-resistant liver.
  • Inhibition of the ER stress in obese rodents decreases SREBP-1c activation and improves
  • hepatic steatosis and insulin sensitivity.

ER is thus a new partner in steatosis and metabolic syndrome

5. Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model
Jin-Sook Leea, Ze Zhenga, R Mendeza, Seung-Wook Hac, et al.
Wayne State University SOM, Detroit, MI
Toxicology Letters 20 May 2012; 211(1):29–38      http://dx.doi.org/10.1016/j.toxlet.2012.02.017

Endoplasmic reticulum (ER) stress refers to a condition of

  •  accumulation of unfolded or misfolded proteins in the ER lumen, which is known to
  • activate an intracellular stress signaling termed
  • Unfolded Protein Response (UPR).

A number of pharmacologic reagents or pathophysiologic stimuli

  •  can induce ER stress and activation of the UPR signaling,
  • leading to alteration of cell physiology that is
  • associated with the initiation and progression of a variety of diseases.

Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis and inflammation, has been considered the
precursor or the hepatic manifestation of metabolic disease. In this study, we delineated the

  • toxic effect and molecular basis
  • by which pharmacologic ER stress,
  • induced by a bacterial nucleoside antibiotic tunicamycin (TM),
  • promotes NASH in an animal model.

Mice of C57BL/6J strain background were challenged with pharmacologic ER stress by intraperitoneal injection of TM. Upon TM injection,

  •  mice exhibited a quick NASH state characterized by
  • hepatic steatosis and inflammation.

TM-treated mice exhibited an increase in –

  •  hepatic triglycerides (TG) and a –
  • decrease in plasma lipids, including
  • plasma TG,
  • plasma cholesterol,
  • high-density lipoprotein (HDL), and
  • low-density lipoprotein (LDL),

In response to TM challenge,

  •  cleavage of sterol responsive binding protein (SREBP)-1a and SREBP-1c,
  •  the key trans-activators for lipid and sterol biosynthesis,
  • was dramatically increased in the liver.

Consistent with the hepatic steatosis phenotype, expression of

  •  some key regulators and enzymes in de novo lipogenesis and lipid droplet formation was up-regulated,
  • while expression of those involved in lipolysis and fatty acid oxidation was down-regulated
  • in the liver of mice challenged with TM.

TM treatment also increased phosphorylation of NF-κB inhibitors (IκB),

  •  leading to the activation of NF-κB-mediated inflammatory pathway in the liver.

Our study not only confirmed that pharmacologic ER stress is a strong “hit” that triggers NASH, but also demonstrated

  •  crucial molecular links between ER stress,
  • lipid metabolism, and
  • inflammation in the liver in vivo.

► Pharmacologic ER stress induced by tunicamycin (TM) induces a quick NASH state in vivo.
► TM leads to dramatic increase in cleavage of sterol regulatory element-binding protein in the liver.
► TM up-regulates lipogenic genes, but down-regulates the genes in lipolysis and FA oxidation.
► TM activates NF-κB and expression of genes encoding pro-inflammatory cytokines in the liver.
ER, endoplasmic reticulum; TM, tunicamycin; NASH, non-alcoholic steatohepatitis; NAFLD,
non-alcoholic fatty liver disease; TG, triglycerides; SREBP, sterol responsive binding protein;
NF-κB, activation of nuclear factor-kappa B; IκB, NF-κB inhibitor
Keywords: ER stress; Non-alcoholic steatohepatitis; Tunicamycin; Lipid metabolism; Hepatic inflammation
Figures and tables from this article:

Fig. 1. TM challenge alters lipid profiles and causes hepatic steatosis in mice. (A) Quantitative real-time RT-PCR analysis of liver mRNA isolated from mice challenged with TM or vehicle control. Total liver mRNA was isolated at 8 h or 30 h after injection with vehicle or TM (2 μg/g body weight) for real-time RT-PCR analysis. Expression values were normalized to β-actin mRNA levels. Fold changes of mRNA are shown by comparing to one of the control mice. Each bar denotes the mean ± SEM (n = 4 mice per group); **P < 0.01. Edem1, ER degradation enhancing, mannosidase alpha-like 1. (B) Oil-red O staining of lipid droplets in the livers of the mice challenged with TM or vehicle control (magnification: 200×). (C) Levels of TG in the liver tissues of the mice challenged with TM or vehicle control. (D) Levels of plasma lipids in the mice challenged with TM or vehicle control. TG, triglycerides; TC, total plasma cholesterol; HDL, high-density lipoproteins; VLDL/LDL, very low and low density lipoproteins. For C and D, each bar denotes mean ± SEM (n = 4 mice per group); *P < 0.05; **P < 0.01.

 Fhttp://ars.els-cdn.com/content/image/1-s2.0-S0378427412000732-gr1.jpgigure options

Fig. 2. TM challenge leads to a quick NASH state in mice. (A) Histological examination of liver tissue sections of the mice challenged with TM (2 μg/g body weight) or vehicle control. Upper panel, hematoxylin–eosin (H&E) staining of liver tissue sections; the lower panel, Sirius staining of collagen deposition of liver tissue sections (magnification: 200×). (B) Histological scoring for NASH activities in the livers of the mice treated with TM or vehicle control. The grade scores were calculated based on the scores of steatosis, hepatocyte ballooning, lobular and portal inflammation, and Mallory bodies. The stage scores were based on the liver fibrosis. Number of mice examined is given in parentheses. Mean ± SEM values are shown. P-values were calculated by Mann–Whitney U-test.


Fig. 3. TM challenge significantly increases levels of cleaved/activated forms of SREBP1a and SREBP1c in the liver. Western blot analysis of protein levels of SREBP1a (A) and SREBP1c (B) in the liver tissues from the mice challenged with TM (2 μg/g body weight) or vehicle control. Levels of GAPDH were included as internal controls. For A and B, the values below the gels represent the ratios of mature/cleaved SREBP signal intensities to that of SREBP precursors. The graph beside the images showed the ratios of mature/cleaved SREBP to precursor SREBP in the liver of mice challenged with TM or vehicle. The protein signal intensities shown by Western blot analysis were quantified by NIH imageJ software. Each bar represents the mean ± SEM (n = 3 mice per group); **P < 0.01. SREBP-p, SREBP precursor; SREBP-m, mature/cleaved SREBP.


Fig. 4. TM challenge up-regulates expression of genes involved in lipogenesis but down-regulates expression of genes involved in lipolysis and FA oxidation. Quantitative real-time RT-PCR analysis of liver mRNAs isolated from the mice challenged with TM (2 μg/g body weight) or vehicle control, which encode regulators or enzymes in: (A) de novo lipogenesis: PGC1α, PGC1β, DGAT1 and DGAT2; (B) lipid droplet production: ADRP, FIT2, and FSP27; (C) lipolysis: ApoC2, Acox1, and LSR; and (D) FA oxidation: PPARα. Expression values were normalized to β-actin mRNA levels. Fold changes of mRNA are shown by comparing to one of the control mice. Each bar denotes the mean ± SEM (n = 4 mice per group); **P < 0.01. (E and F) Isotope tracing analysis of hepatic de novo lipogenesis. Huh7 cells were incubated with [1-14C] acetic acid for 6 h (E) or 12 h (F) in the presence or absence of TM (20 μg/ml). The rates of de novo lipogenesis were quantified by determining the amounts of [1-14C]-labeled acetic acid incorporated into total cellular lipids after normalization to cell numbers.


Fig. 5. TM activates the inflammatory pathway through NF-κB, but not JNK, in the liver. Western blot analysis of phosphorylated Iκ-B, total Iκ-B, phosphorylated JNK, and total JNK in the liver tissues from the mice challenged with TM (2 μg/g body weight) or vehicle control. Levels of GAPDH were included as internal controls. The values below the gels represent the ratios of phosphorylated protein signal intensities to that of total proteins.


Fig. 6. TM induces expression of pro-inflammatory cytokines and acute-phase responsive proteins in the liver. Quantitative real-time RT-PCR analyses of liver mRNAs isolated from the mice challenged with TM (2 μg/g body weight) or vehicle control, which encode: (A) pro-inflammatory cytokine TNFα and IL6; and (B) acute-phase protein SAP and SAA3. Expression values were normalized to β-actin mRNA levels. Fold changes of mRNA are shown by comparing to one of the control mice. (C–E) ELISA analyses of serum levels of TNFα, IL6, and SAP in the mice challenged with TM or vehicle control for 8 h ELISA. Each bar denotes the mean ± SEM (n = 4 mice per group); *P < 0.05, **P < 0.01.


Corresponding author at: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, USA. Tel.: +1 313 577 2669; fax: +1 313 577 5218.

The SREBP regulatory pathway. Brown MS, Goldst...

The SREBP regulatory pathway. Brown MS, Goldstein JL (1997). “The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor”. Cell 89 (3) : 331–340. doi:10.1016/S0092-8674(00)80213-5. PMID 9150132. (Photo credit: Wikipedia)

English: Structure of the SREBF1 protein. Base...

English: Structure of the SREBF1 protein. Based on PyMOL rendering of PDB 1am9. (Photo credit: Wikipedia)

The SREBP regulatory pathway

The SREBP regulatory pathway (Photo credit: Wikipedia)

English: Diagram of rough endoplasmic reticulu...

English: Diagram of rough endoplasmic reticulum by Ruth Lawson, Otago Polytechnic. (Photo credit: Wikipedia)

Micrograph demonstrating marked (macrovesicula...

Micrograph demonstrating marked (macrovesicular) steatosis in non-alcoholic fatty liver disease. Masson’s trichrome stain. (Photo credit: Wikipedia)


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Reporter: Aviva Lev-Ari, PhD, RN


The role of the saturated non-esterified fatty acid palmitate in beta cell dysfunction

J. Proteome Res., Just Accepted Manuscript
DOI: 10.1021/pr300596g
Publication Date (Web): November 21, 2012
Copyright © 2012 American Chemical Society


Sustained elevated levels of saturated free fatty acids, such as palmitate, contribute to beta cell dysfunction, a phenomenon aggravated by high glucose levels.

The aim of this study was to investigate the mechanisms of palmitate-induced beta cell dysfunction and death, combined or not with high glucose. Protein profiling of INS-1E cells, exposed to 0.5 mmol/l palmitate and combined or not with 25 mmol/l glucose, for 24 h was done by 2D-DIGE, both on full cell lysate and on an enriched endoplasmic reticulum (ER) fraction. 83 differentially expressed proteins (P < 0.05) were identified by MALDI-TOF/TOF mass spectrometry and proteomic results were confirmed by functional assays. 2D-DIGE analysis of whole cell lysates and ER enriched samples revealed a high number of proteins compared to previous reports. Palmitate induced beta cell dysfunction and death via ER stress, hampered insulin maturation, generation of harmful metabolites during triglycerides synthesis and altered intracellular trafficking. In combination with high glucose, palmitate induced increased shunting of excess glucose, increased mitochondrial reactive oxygen species production and an elevation in many transcription-related proteins. This study contributes to a better understanding and revealed novel mechanisms of palmitate-induced beta cell dysfunction and death and may provide new targets for drug discovery.





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