No 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 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 Zn 2+ 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 pH close to neutral, i.e. in the pH range found in the early secretory pathway, while it is resolved at acidic pH and Zn 2+ concentrations resembling those present in mature