title: Insulin biosynthetic interaction network component, TMEM24, facilitates insulin reserve pool release.
abstract: Insulin homeostasis in pancreatic β cells is now recognized as a critical element in the progression of obesity and type II diabetes (T2D). Proteins that interact with insulin to direct its sequential synthesis, folding, trafficking, and packaging into reserve granules in order to manage release in response to elevated glucose remain largely unknown. Using a conformation-based approach combined with mass spectrometry, we have generated the insulin biosynthetic interaction network (insulin BIN), a proteomic roadmap in the β cell that describes the sequential interacting partners of insulin along the secretory axis. The insulin BIN revealed an abundant C2 domain-containing transmembrane protein 24 (TMEM24) that manages glucose-stimulated insulin secretion from a reserve pool of granules, a critical event impaired in patients with T2D. The identification of TMEM24 in the context of a comprehensive set of sequential insulin-binding partners provides a molecular description of the insulin secretory pathway in β cells.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Pottekat
authors.forename: Scott
authors.initials: S
authors.lastname: Becker
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Spencer
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
authors.forename: Pamela
authors.initials: P
authors.lastname: Itkin-Ansari
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: C498365:C2cd2l protein, mouse; D007328:Insulin; D008565:Membrane Proteins