title: Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate.
abstract: Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer's disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia.
authors: Amgen, Cardiometabolic Disorders, South San Francisco, California, United States of America.
authors: Ingrid C
authors: IC
authors: Rulifson
authors: Amgen, Molecular Structure and Characterization, South San Francisco, California, United States of America.
authors: Ping
authors: P
authors: Cao
authors: Amgen, Cardiometabolic Disorders, South San Francisco, California, United States of America.
authors: Li
authors: L
authors: Miao
authors: Amgen, Medicinal Chemistry, Thousand Oaks, California, United States of America.
authors: David
authors: D
authors: Kopecky
authors: Amgen, Molecular Structure and Characterization, South San Francisco, California, United States of America.
authors: Linda
authors: L
authors: Huang
authors: Amgen, Medicinal Chemistry, Cambridge, Massachusetts, United States of America.
authors: Ryan D
authors: RD
authors: White
authors: Amgen, Pathology, South San Francisco, California, United States of America.
authors: Kim
authors: K
authors: Samayoa
authors: Amgen, Cardiometabolic Disorders, South San Francisco, California, United States of America.
authors: Jonitha
authors: J
authors: Gardner
authors: Amgen, Cardiometabolic Disorders, South San Francisco, California, United States of America.
authors: Xiaosu
authors: X
authors: Wu
authors: Amgen, Discovery Technologies, Thousand Oaks, California, United States of America.
authors: Kui
authors: K
authors: Chen
authors: Amgen, Biologics, Thousand Oaks, California, United States of America.
authors: Trace
authors: T
authors: Tsuruda
authors: Amgen, Genome Analysis Unit, South San Francisco, California, United States of America.
authors: Oliver
authors: O
authors: Homann
authors: Amgen, Cardiometabolic Disorders, South San Francisco, California, United States of America.
authors: Helene
authors: H
authors: Baribault
authors: Amgen, Biologics, Thousand Oaks, California, United States of America.
authors: Harvey
authors: H
authors: Yamane
authors: Amgen, Pharmacokinetics and Drug Metabolism, South San Francisco, California, United States of America.
authors: Tim
authors: T
authors: Carlson
authors: Amgen, Genome Analysis Unit, South San Francisco, California, United States of America.
authors: Jed
authors: J
authors: Wiltzius
authors: Amgen, Cardiometabolic Disorders, South San Francisco, California, United States of America.
authors: Yang
authors: Y
authors: Li
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D058225:Plaque, Amyloid / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011994:Recombinant Proteins; D013379:Substrate Specificity
chemical_list: D007328:Insulin; D058228:Islet Amyloid Polypeptide; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human