Condensation properties of proteins involved in the insulin secretory granules

MILAGROS B. ABATE; PAMELA L. TOLEDO; ALEJO R. GIANOTTI; JUHA TORKKO; MICHELE SOLIMENA; DIEGO S. VAZQUEZ; MARIO R. ERMÁCORA

Cordoba

Congreso; LI Reunión Anual de la Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

Insulin is one of the primary factors in secretory granules (SGs) in pancreatic β-cells. This peptide hormone regulates glucose uptake and utilization in the body´s cells. Thus, hyperglycemia, commonly associated with diabetes mellitus, occurs due to insufficient insulin production or resistance to insulin activity.ICA512 is a R8-subtype protein tyrosine phosphatases (RPTPs) enriched in the membrane of SGs in pancreatic β-cells and other neuroendocrine cells. ICA512 is involved in the biogenesis and turnover of insulin SGs, among other proteins. The N-terminal luminal segment of this protein includes a region with sequence similarity to the Regulated endocrine-specific protein 18 (Resp18). Our focus is on the homologous region of ICA512, hereinafter named Resp18 Homology Domain (RESP18HD). In previous studies we have identified the role of the RESP18HD131 variant as an insulin fibrillation inhibitor1. This process can be described by the optics of biomolecular condensates. These are defined as clusters of non-stoichiometric biomolecules linked by non-covalent interactions, which could evolve to micrometre-sized objects2.This study focuses on the condensation and structural properties of different variants of RESP18HD with proinsulin, the physiological precursor of insulin. Preliminary results suggest that under conditions that mimic the physicochemical environment of SGs, RESP18HD forms biomolecular condensates in the co-aggregation reaction with proinsulin. These mesoscopic-sized clusters are the precursors of amorphous aggregates that may be associated with the process of insulin-SG maturation in the secretory pathway.