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Toledo, P.L.* ; Torkko, J.M. ; Müller, A. ; Wegbrod, C. ; Sönmez, A. ; Solimena, M. ; Ermácora, M.R.*

ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor.

J. Biol. Chem. 294, 8564-8576 (2019)
Verlagsversion Postprint Forschungsdaten DOI
Open Access Green
Type 1 diabetes islet cell autoantigen 512 (ICA512/IA-2) is a tyrosine phosphatase-like intrinsic membrane protein involved in the biogenesis and turnover of insulin secretory granules (SGs) in pancreatic islet -cells. Whereas its membrane-proximal and cytoplasmic domains have been functionally and structurally characterized, the role of the ICA512 N-terminal segment named regulated endocrine-specific protein 18 homology domain (RESP18HD), which encompasses residues 35-131, remains largely unknown. Here, we show that ICA512 RESP18HD residues 91-131 encode for an intrinsically disordered region (IDR), which in vitro acts as a condensing factor for the reversible aggregation of insulin and other -cell proteins in a pH and Zn2+-regulated fashion. At variance with what has been shown for other granule cargoes with aggregating properties, the condensing activity of ICA512 RESP18HD is displayed at a pH close to neutral, i.e. in the pH range found in the early secretory pathway, whereas it is resolved at acidic pH and Zn2+ concentrations resembling those present in mature SGs. Moreover, we show that ICA512 RESP18HD residues 35-90, preceding the IDR, inhibit insulin fibrillation in vitro. Finally, we found that glucose-stimulated secretion of RESP18HD upon exocytosis of SGs from insulinoma INS-1 cells is associated with cleavage of its IDR, conceivably to prevent its aggregation upon exposure to neutral pH in the extracellular milieu. Taken together, these findings point to ICA512 RESP18HD being a condensing factor for protein sorting and granulogenesis early in the secretory pathway and for prevention of amyloidogenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Aggregation ; Amyloid ; Insulin Secretion ; Secretion ; Diabetes ; Trafficking ; Ia-2 ; Ica512 ; Protein Targeting ; Ptprn ; Secretory Granule; Secretory Granules; Targeted Disruption; Mature Ectodomain; Membrane-protein; Phase-separation; Islet Cells; Beta-cells; Glucose; Expression; Ia-2
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Quellenangaben Band: 294, Heft: 21, Seiten: 8564-8576 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)