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Understanding the mechanism of amylin aggregation: From identifying crucial segments to tracing dominant sequential events to modeling potential aggregation suppressors.
Biochim Biophys Acta Proteins Proteom
January 2023
Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address:
One of the most abundant, prevailing, and life-threatening human diseases that are currently baffling the scientific community is type 2 diabetes (T2D). The self-association of human amylin has been implicated in the pathogenesis of T2D, though with an inconclusive understanding of the mechanism. Hence, we focused on the characterization of the conformational ensembles of all the species that are believed to define the structural polymorphism of the aggregation process - the functional monomeric, the initially self-associated oligomeric, and the structured protofibril - by employing near-equilibrium, non-equilibrium, and equilibrium atomistic simulations on the sporadic, two familial variants (S20G and G33R), and their proline-substituted forms (S20P and G33P).
View Article and Find Full Text PDFStructural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide.
Biochim Biophys Acta Gen Subj
August 2021
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil; Porto Reports, Brasília, DF, Brazil. Electronic address:
Article Synopsis
- - Amylin, a hormone that works alongside insulin and is linked to glucose control, can form aggregates associated with type II diabetes, and its gene has variants caused by point mutations that may affect its function.
- - This study focused on the S20G and G33R mutations, common in East Asian and European populations, using various analytical methods to assess their structural effects on amylin and their aggregation potential compared to the normal form.
- - Results indicated that both mutations alter amylin's structure and may have negative impacts on its function, suggesting potential new avenues for diabetes treatment aimed at addressing these specific mutations.
Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly.
Nat Struct Mol Biol
November 2020
Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, University of Leeds, Leeds, UK.
Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G mutation in amylin is associated with early-onset T2D. Here we report cryo-EM structures of amyloid fibrils of wild-type human amylin and its S20G variant.
View Article and Find Full Text PDFCryo-EM structure and inhibitor design of human IAPP (amylin) fibrils.
Nat Struct Mol Biol
July 2020
Department of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, and Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM structure of recombinant full-length hIAPP fibrils. The fibril is composed of two symmetrically related protofilaments with ordered residues 14-37.
View Article and Find Full Text PDFEvolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears?
Isr J Chem
July 2017
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400.
Much of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid-rich diet without deleterious metabolic consequences.
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