Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient &nbsp;-sheet

Buchanan, L. E.; Dunkelberger, E. B.; Tran, H. Q.; Cheng, P. -N.; Chiu, C. -C.; Cao, P.; Raleigh, D. P.; de Pablo, J. J.; Nowick, J. S.; Zanni, M. T.

doi:10.1073/pnas.1314481110

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient -sheet

Journal Article · Mon Nov 11 04:00:00 EST 2013 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1314481110· OSTI ID:1395109

Buchanan, L. E.; Dunkelberger, E. B.; Tran, H. Q.; Cheng, P. -N.; Chiu, C. -C.; Cao, P.; Raleigh, D. P.; de Pablo, J. J.; Nowick, J. S.; Zanni, M. T.

Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.

Research Organization:: Argonne National Laboratory (ANL)

Sponsoring Organization:: National Science Foundation (NSF); National Institutes of Health (NIH); USDOE Office of Science - Office of Basic Energy Sciences - Materials Sciences and Engineering Division

DOE Contract Number:: AC02-06CH11357

OSTI ID:: 1395109

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 48 Vol. 110; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)

Country of Publication:: United States

Language:: English

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