ICA512/IA-2 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor

TOLEDO, PAMELA L.; WEGBROD, CAROLIN; ERMÁCORA, MARIO R.; TORKKO, JUHA M.; MÜLLER ANDREAS; SOLIMENA, MICHELE; SÖNMEZ, ANKE

Düsseldorf

Workshop; DZD-German Center for Diabetes Research Workshop; 2019

DZD

Type 1 diabetes islet cell autoantigen ICA512/IA-2/PTPRN is a catalytically inactive receptor protein tyrosine phosphatase (PTP) and an intrinsic transmembrane protein of the pancreatic islet β-cell insulin secretory granules (SGs) that is involved in the SG biogenesis and turnover. Whereas the ICA512 luminal membrane proximal ectodomain (MPE) has been functionally and structurally characterized, the role of its preceding N-terminal luminal segment, termed regulated endocrine‑specific protein 18-homology domain (RESP18HD) encompassing amino acids 35-131 remains largely unknown.Here we show that ICA512 RESP18HD C-terminal motif including amino acid residues 91-131 contains an intrinsically disordered region (IDR), which is critically required for RESP18HD function as a pH and Zn2+ dependent condensation and reversible aggregation factor for insulin and other β-cell proteins. ? Moreover, we show that the ICA512 RESP18HD portion including amino acid residues 35-90, i.e. the region preceding the IDR, facilitates inhibition of insulin fibrillation in vitro. ? Finally, we show that glucose-stimulated release of ICA512 RESP18HD from the SGs is associated with proteolysis of its IDR, conceivably to prevent its aggregation upon exposure to neutral pH in the extracellular milieu.