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

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 b-cells. Whereas its membrane-proximal and cytoplasmic domains have been functionally and...

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Detalles Bibliográficos
Autores principales: Toledo, Pamela, Torkko, Juha M., Müller, Andreas, Wegbrod, Carolin, Sönmez, Anke, Solimena, Michele, Ermácora, Mario Roberto
Formato: Articulo
Lenguaje:Inglés
Publicado: 2019
Materias:
Química
Biología
Aggregation
Amyloid
Insulin secretion
Diabetes
Trafficking
IA-2
Protein targeting
PTPRN
Secretory granule
ICA512
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/107008
http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6544868&blobtype=pdf
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-107008
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Química
Biología
Aggregation
Amyloid
Insulin secretion
Diabetes
Trafficking
IA-2
Protein targeting
PTPRN
Secretory granule
ICA512
spellingShingle Química
Biología
Aggregation
Amyloid
Insulin secretion
Diabetes
Trafficking
IA-2
Protein targeting
PTPRN
Secretory granule
ICA512
Toledo, Pamela
Torkko, Juha M.
Müller, Andreas
Wegbrod, Carolin
Sönmez, Anke
Solimena, Michele
Ermácora, Mario Roberto
ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
topic_facet Química
Biología
Aggregation
Amyloid
Insulin secretion
Diabetes
Trafficking
IA-2
Protein targeting
PTPRN
Secretory granule
ICA512
description 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 b-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 b-cell proteins in a pH and Zn21-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 Zn21 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.
format Articulo
Articulo
author Toledo, Pamela
Torkko, Juha M.
Müller, Andreas
Wegbrod, Carolin
Sönmez, Anke
Solimena, Michele
Ermácora, Mario Roberto
author_facet Toledo, Pamela
Torkko, Juha M.
Müller, Andreas
Wegbrod, Carolin
Sönmez, Anke
Solimena, Michele
Ermácora, Mario Roberto
author_sort Toledo, Pamela
title ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
title_short ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
title_full ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
title_fullStr ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
title_full_unstemmed ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
title_sort ica512 resp18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor
publishDate 2019
url http://sedici.unlp.edu.ar/handle/10915/107008
http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6544868&blobtype=pdf
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