Human islet amyloid polypeptide monomers form ordered beta-hairpins: a possible direct amyloidogenic precursor.
Oligomerization of human islet amyloid polypeptide (IAPP) has been increasingly considered a pathogenic process in type II diabetes. Here structural features of the IAPP monomer have been probed using a combination of ion mobility mass spectrometry (IMS-MS) and all-atom replica exchange molecular dynamics (REMD) simulations. Three distinct conformational families of human IAPP monomer are observed in IMS experiments, and two of them are identified as dehydrated solution structures on the basis of our simulation results: one is an extended beta-hairpin structural family, and the second is a compact helix-coil structural family. The extended beta-hairpin family is topologically similar to the peptide conformation in the solid-state NMR fibril structure published by Tycko and co-workers. It is absent in both experiments and simulations performed on the non-amyloidogenic rat IAPP, suggesting it may play an important role in the fibrillation pathway of human IAPP. In addition, pH dependence studies show that the relative abundance of the beta-hairpin structural family is significantly enhanced at pH 8.0. This observation is consistent with the increased rate of fibrillation at high pH in vitro and offers a possible explanation of the pH dependent fibrillation in vivo. This paper, to the best of our knowledge, presents the first experimental evidence of a significant population of beta-hairpin conformers for the IAPP peptide. It is consistent with a previous suggestion in the literature that beta-sheet-rich oligomers are assembled from ordered beta-hairpins rather than from coiled structures.
Dupuis
Nicholas F
NF
Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, USA.
Wu
Chun
C
Shea
Joan-Emma
JE
Bowers
Michael T
MT
D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007515:Islets of Langerhans / Q000737:chemistry*; D013058:Mass Spectrometry; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats
D000682:Amyloid