Leaders in Pharmaceutical Business Intelligence (LPBI) Group

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

http://sandwalk.blogspot.com/2007/02/anfinsen-experiment-in-protein-folding.html

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.

http://www.laskerfoundation.org/awards/2014_b_interview_mori.htm

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.

https://youtu.be/cvE6Kia0T9E

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

http://www.laskerfoundation.org/awards/2014_b_description.htm

http://www.jci.org/articles/view/78419

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

https://youtu.be/3lSsNdP_Mmc

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.

http://www.the-scientist.com/?articles.view/articleNo/40946/title/Lasker-Winners-Announced/

2014Life Science and MedicineProfessor Kazutoshi Mori and Professor Peter Walter

http://www.shawprize.org/en/shaw.php?tmp=4&twoid=97&threeid=238&fourid=428

https://youtu.be/NgW6WvMgj2s

World’s Largest Protein Interaction Map Created

GEN News  Sep 8, 2015
http://www.genengnews.com/gen-news-highlights/world-s-largest-protein-interaction-map-created/81251700/

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

http://www.genengnews.com/Media/images/GENHighlight/thumb_Sep8_2015_iStock_26507385_protein5412011712.jpg

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

http://www.biosciencetechnology.com/news/2015/09/hormone-injections-may-have-spread-seeds-alzheimers-study-says?et_cid=4808735&et_rid=535648082&type=cta

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

http://www.rdmag.com/videos/2015/08/chemists-solve-major-piece-cellular-mystery?et_cid=4775862&et_rid=535648082&location=top

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

Jiang Wang and Andrew L. Ferguson

Phys. Rev. E 93, 032412 – Published 21 March 2016     http://dx.doi.org/10.1103/PhysRevE.93.032412