Aging Proteins
Larry H Bernstein, MD, FCAP, Curator
LPBI
How Proteins Betray Their Age, Succumb to Forced Retirement
- In the blood and other circulating fluids, proteins stay on the job only as long as they can maintain a youthful appearance. When proteins start showing the equivalent of gray around the temples—degraded N-glycan linkages—they are soon ushered out of the proteomic workforce, however able-bodied they might be.
- This finding, which appeared October 21 in the Proceedings of the National Academy of Sciences (PNAS), suggests that it might be possible to extend the working lives of proteins, or force proteins into early retirement—adjusting the composition of the proteomic workforce to promote health while sidelining or terminating disease processes.
As secreted proteins age their attached complex N-glycans undergo a progressive enzymatic loss of sugar linkages, one at a time, leading to the appearance of signals of increased age that determine a protein’s life span. [Peter Allen, UCSB]
- The aging and turnover of secreted proteins, it turns out, encompasses multiple factors, including circulating enzymes called glycosidases. These enzymes progressively remodel N-glycans, which are complex structures of monosaccharide sugars linked together and attached to virtually all secreted proteins.
- Over time, sugar linkage by sugar linkage, the N-glycans that initially grace proteins lose their sheen and become increasingly coarse. Then the proteins run afoul of endocytic lectins, which are carbohydrate-binding receptors. Essentially, these lectins recognize aged proteins and eliminate them from circulation.
- Details of this protein-culling process were uncovered by scientists at the University of California, Santa Barbara (UCSB) and the Sanford-Burnham-Prebys (SBP) Medical Discovery Institute. These scientists, led by Jamey Marth, Ph.D., a researcher affiliated with both institutions, summarized their results in the PNAS paper, which was entitled, “An intrinsic mechanism of secreted protein aging and turnover.”
- “Endogenous glycosidases, including neuraminidase 1 (Neu1), neuraminidase 3 (Neu3), beta-galactosidase 1 (Glb1), and hexosaminidase B (HexB), possess hydrolytic activities that temporally remodel N-glycan structures, progressively exposing different saccharides with increased protein age,” the article’s authors wrote. “Subsequently, endocytic lectins with distinct binding specificities, including the Ashwell–Morell receptor, integrin αM, and macrophage mannose receptor, are engaged in N-glycan ligand recognition and the turnover of secreted proteins.”
- The authors also noted that glycosidase inhibition and lectin deficiencies could increase protein life spans and abundance. Finally, they determined that the basal rate of N-glycan remodeling varied among distinct proteins, accounting for differences in their life spans.
- “When a secreted protein is made, it has a useful life span and then it must be degraded—the components are then basically recycled,” said Dr. Marth. “We can now see how the regulation and alteration of secreted protein aging and turnover is able to change the composition of the circulatory system and thereby maintain health as well as contribute to various diseases.”
- “The discovery of this mechanism provides a unique window into disease origins and progression,” Dr. Marth continued. “It has been known that circulating glycosidase enzyme levels are altered in diseases such as sepsis, diabetes, cancer, and various inflammatory conditions. The resulting changes in the composition and function of the circulatory systems, including the blood and the lymphatic systems, can now be identified and studied. We are beginning to see previously unknown molecular pathways and connections in the onset and progression of disease.”
- Dr. Marth added that altering the protein aging and turnover mechanism “is the fastest way to change the abundance of a secreted protein,” a quantity that is increasingly recognized as having significance at the interface of health and disease.
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This is very insightful. There is no doubt that there is the bias you refer to. 42 years ago, when I was postdocing in biochemistry/enzymology before completing my residency in pathology, I knew that there were very influential mambers of the faculty, who also had large programs, and attracted exceptional students. My mentor, it was said (although he was a great writer), could draft a project on toilet paper and call the NIH. It can’t be true, but it was a time in our history preceding a great explosion. It is bizarre for me to read now about eNOS and iNOS, and about CaMKII-á, â, ã, ä – isoenzymes. They were overlooked during the search for the genome, so intermediary metabolism took a back seat. But the work on protein conformation, and on the mechanism of action of enzymes and ligand and coenzyme was just out there, and became more important with the research on signaling pathways. The work on the mechanism of pyridine nucleotide isoenzymes preceded the work by Burton Sobel on the MB isoenzyme in heart. The Vietnam War cut into the funding, and it has actually declined linearly since.
A few years later, I was an Associate Professor at a new Medical School and I submitted a proposal that was reviewed by the Chairman of Pharmacology, who was a former Director of NSF. He thought it was good enough. I was a pathologist and it went to a Biochemistry Review Committee. It was approved, but not funded. The verdict was that I would not be able to carry out the studies needed, and they would have approached it differently. A thousand young investigators are out there now with similar letters. I was told that the Department Chairmen have to build up their faculty. It’s harder now than then. So I filed for and received 3 patents based on my work at the suggestion of my brother-in-law. When I took it to Boehringer-Mannheim, they were actually clueless.