title: Orientations of residues along the β-arch of self-assembled amylin fibril-like structures lead to polymorphism.
abstract: Amylin is an endocrine hormone peptide that consists of 37 residues and is the main component of extracellular amyloid deposits found in the pancreas of most type 2 diabetes patients. Amylin peptides are self-assembled to form oligomers and fibrils. So far, four different molecular structures of the self-assembled amylin fibrils have been observed experimentally: two ssNMR models and two crystal models. This study reveals, for the first time, that there are four self-assembled amylin forms that differ in the orientations of the side chains along the β-arch and are all derived from the two ssNMR models. The two ssNMR models are composed of these four different self-assembled forms of amylin, and the two crystal models are composed of two different self-assembled forms of amylin. This study illustrates at the atomic level the differences among the four experimental models and proposes eight new models of self-assembled amylin that are also composed of the four different self-assembled forms of amylin. Our results show polymorphism of the self-assembled fibril-like amylin, with a slight preference of some of the newly constructed models over the experimental models. Finally, we propose that two different self-assembled fibril-like forms of amylin can interact to form a new fibril-like amylin. We investigated this argument and found that some fibril-like amylin prefers to interact to form stable fibril-like structures, whereas others disfavor it. Our work provides new insights that may suggest strategies for future pharmacological studies that aim to find ways to ameliorate the interactions between polymorphic oligomers and fibrils of amylin.
authors.affiliation: Department of Chemistry and Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev , Beer-Sheva 84105, Israel.
authors.forename: Vered
authors.initials: V
authors.lastname: Wineman-Fisher
authors.forename: Yoav
authors.initials: Y
authors.lastname: Atsmon-Raz
authors.forename: Yifat
authors.initials: Y
authors.lastname: Miller
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide