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Toledo, P.L.* ; Vazquez, D.S.* ; Gianotti, A.R.* ; Abate, M.B.* ; Wegbrod, C. ; Torkko, J.M. ; Solimena, M. ; Ermácora, M.R.*

Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain.

Protein Sci. 32:e4649 (2023)
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ICA512/PTPRN is a receptor tyrosine-like phosphatase implicated in the biogenesis and turnover of the insulin secretory granules (SGs) in pancreatic islet beta cells. Previously we found biophysical evidence that its luminal RESP18 homology domain (RESP18HD) forms a biomolecular condensate and interacts with insulin in vitro at close-to-neutral pH, that is, in conditions resembling those present in the early secretory pathway. Here we provide further evidence for the relevance of these findings by showing that at pH 6.8 RESP18HD interacts also with proinsulin-the physiological insulin precursor found in the early secretory pathway and the major luminal cargo of β-cell nascent SGs. Our light scattering analyses indicate that RESP18HD and proinsulin, but also insulin, populate nanocondensates ranging in size from 15 to 300 nm and 10e2 to 10e6 molecules. Co-condensation of RESP18HD with proinsulin/insulin transforms the initial nanocondensates into microcondensates (size >1 μm). The intrinsic tendency of proinsulin to self-condensate implies that, in the ER, a chaperoning mechanism must arrest its spontaneous intermolecular condensation to allow for proper intramolecular folding. These data further suggest that proinsulin is an early driver of insulin SG biogenesis, in a process in which its co-condensation with RESP18HD participates in their phase separation from other secretory proteins in transit through the same compartments but destined to other routes. Through the cytosolic tail of ICA512, proinsulin co-condensation with RESP18HD may further orchestrate the recruitment of cytosolic factors involved in membrane budding and fission of transport vesicles and nascent SGs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Insulin ; Mesoscopic Clusters ; Nanocondensates ; Proinsulin ; Protein Secretion ; Protein Sorting ; Protein Tyrosine Phosphatase ; Protein-protein Interactions ; Secretory Granule Biogenesis ; β Cell; Liquid-phase-separation; Carboxypeptidase-e; Membrane-protein; Insulin; Proinsulin; Trafficking; Mechanism; Biosynthesis; Conformation; Thioredoxin
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 0961-8368
e-ISSN 1469-896X
Journal Protein Science
Quellenangaben Volume: 32, Issue: 6, Pages: , Article Number: e4649 Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502600-001
Grants Universidad Nacional de Quilmes
Swiss State Secretariat for Education, Research and Innovation
Innovative Medicines Initiative 2 Joint Undertaking
German Ministry of Education and Research
German Center for Diabetes Research (DZD)
European Union
Consejo Nacional de Investigaciones Cientificas y Tecnicas
Agencia Nacional de Promoción Científica y Tecnológica
DOI 10.1002/pro.4649
WOS ID 000993380300001
Scopus ID 85160873193
PubMed ID 37159024
Erfassungsdatum 2023-10-06
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