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J Biol Chem. 2019 May 24;294(21):8564-8576. doi: 10.1074/jbc.RA119.007607. Epub 2019 Apr 12.

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

Toledo PL1,2, Torkko JM1,2,3,4,5, Müller A3,4,5, Wegbrod C3,4,5, Sönmez A3,4,5, Solimena M6,4,5,7, Ermácora MR8,2.

Author information

1
From the Grupo de Biología Estructural y Biotecnología, Universidad Nacional de Quilmes, 1876 Bernal, Buenos Aires, Argentina.
2
the IMBICE, CONICET-CIC-Universidad Nacional de La Plata, B1906APO La Plata, Buenos Aires, Argentina.
3
the Department of Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany.
4
the Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany.
5
the German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany, and.
6
the Department of Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany, michele.solimena@tu-dresden.de.
7
the Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
8
From the Grupo de Biología Estructural y Biotecnología, Universidad Nacional de Quilmes, 1876 Bernal, Buenos Aires, Argentina, ermacora@unq.edu.ar.

Abstract

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 β-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 β-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.

KEYWORDS:

IA-2; ICA512; PTPRN; aggregation; amyloid; diabetes; insulin secretion; protein targeting; secretion; secretory granule; trafficking

PMID:
30979722
PMCID:
PMC6544868
[Available on 2020-05-24]
DOI:
10.1074/jbc.RA119.007607

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