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

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

Protein conformation and biomolecular condensates

“…Mesoscopic clusters are deemed important precursors in nucleation processes, such as crystallization, irreversible aggregation, and fibrillation; in turn, these nucleation processes characterize many physiological and pathological conditions ( Vekilov, 2004 ; Pan et al., 2010 ; Sleutel and Van Driessche, 2014 ; Sosa et al., 2016 ; Schubert et al., 2017 ; Chan and Lubchenko, 2019 ; Toledo et al., 2019 ; Choi et al., 2020 ; Xu et al., 2021 ; Yang et al., 2021 ; Petronilho et al., 2021 ; Parchure et al., 2021 ). In addition to proteins, amphiphilic amino acids and small organic compounds were shown to form mesoscopic clusters ( Warzecha et al., 2017 ; Yuan et al., 2019 ).…”

Overexpression of PTPRN Promotes Metastasis of Lung Adenocarcinoma and Suppresses NK Cell Cytotoxicity

“…Receptor-type tyrosine-protein phosphatase-like N (PTPRN), also called islet cell autoantigen 512 (ICA512/IA-2), is a tyrosine phosphatase-like intrinsic membrane protein which participates in the biological process of insulin secretory granules in pancreatic islet β-cells ( Toledo et al, 2019 ). It was reported to have a high expression in neuroendocrine cells ( Takeyama et al, 2009 ; Gomi et al, 2013 ) and is related to diabetes ( Steinbrenner et al, 2002 ).…”

Scientific Advances in Diabetes: The Impact of the Innovative Medicines Initiative

“…Novel relevant pathways were proposed to understand β-cell development and function [by IMIDIA ( 109 – 113 ), StemBANCC ( 114 – 119 ), and RHAPSODY ( 27 )], type 1 diabetes (by INNODIA ( 16 , 20 , 23 , 120 – 125 ), type 2 diabetes [by DIRECT ( 50 ), EMIF ( 85 , 126 – 130 ), and Rhapsody ( 131 )], CVD [SUMMIT ( 30 , 132 ) and INNODIA ( 133 )], DKD [BEAT-DKD ( 32 , 36 , 134 – 138 )], DR [SUMMIT ( 30 , 42 , 43 )], endometrial cancer risk [EMIF ( 139 )], dementia [EMIF ( 140 )], non-alcoholic fatty liver disease [EMIF ( 54 , 55 , 141 – 143 )], anorexia or bulimia [INNODIA ( 125 )], and attention-deficit hyperactivity disorder [INNODIA ( 125 )].…”