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Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment.
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Frustrated peptide chains at the fibril tip control the kinetics of growth of amyloid-β fibrils
Amyloid fibrillization is an exceedingly complex process in which incoming peptide chains bind to the fibril while concertedly folding. The coupling between folding and binding is not fully understood. We explore the molecular pathways of association of Aβ40 monomers to fibril tips by combining time-resolved in situ scanning probe microscopy with molecular modeling. The comparison between experimental and simulation results shows that a complex supported by nonnative contacts is present in the equilibrium structure of the fibril tip and impedes fibril growth in a supersaturated solution. The unraveling of this frustrated state determines the rate of fibril growth. The kinetics of growth of freshly cut fibrils, in which the bulk fibril structure persists at the tip, complemented by molecular simulations, indicate that this frustrated complex comprises three or four monomers in nonnative conformations and likely is contained on the top of a single stack of peptide chains in the fibril structure. This pathway of fibril growth strongly deviates from the common view that the conformational transformation of each captured peptide chain is templated by the previously arrived peptide. The insights into the ensemble structure of the frustrated complex may guide the search for suppressors of Aβ fibrillization. The uncovered dynamics of coupled structuring and assembly during fibril growth are more complex than during the folding of most globular proteins, as they involve the collective motions of several peptide chains that are not guided by a funneled energy landscape.
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- Award ID(s):
- 2019745
- PAR ID:
- 10305613
- Publisher / Repository:
- Proceedings of the National Academy of Sciences
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 118
- Issue:
- 38
- ISSN:
- 0027-8424
- Page Range / eLocation ID:
- Article No. e2110995118
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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