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dc.contributor.author
Toledo, Pamela Ludmila
dc.contributor.author
Torkko, Juha Markunpoika
dc.contributor.author
Müller, Andreas
dc.contributor.author
Wegbrod, Carolin
dc.contributor.author
Sönmez, Anke
dc.contributor.author
Solimena, Michele
dc.contributor.author
Ermacora, Mario Roberto
dc.date.available
2021-03-15T18:14:05Z
dc.date.issued
2019-04
dc.identifier.citation
Toledo, Pamela Ludmila; Torkko, Juha Markunpoika; Müller, Andreas; Wegbrod, Carolin; Sönmez, Anke; et al.; ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 294; 21; 4-2019; 8564-8576
dc.identifier.issn
0021-9258
dc.identifier.uri
http://hdl.handle.net/11336/128337
dc.description.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 Zn2+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 Zn2+ 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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Biochemistry and Molecular Biology
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
IA-2
dc.subject
ICA512
dc.subject
PTPRN
dc.subject
aggregation
dc.subject.classification
Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-11-11T15:54:54Z
dc.journal.volume
294
dc.journal.number
21
dc.journal.pagination
8564-8576
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Toledo, Pamela Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
dc.description.fil
Fil: Torkko, Juha Markunpoika. Paul Langerhans Institute Dresden; Alemania
dc.description.fil
Fil: Müller, Andreas. Paul Langerhans Institute Dresden; Alemania
dc.description.fil
Fil: Wegbrod, Carolin. Paul Langerhans Institute Dresden; Alemania
dc.description.fil
Fil: Sönmez, Anke. Paul Langerhans Institute Dresden; Alemania
dc.description.fil
Fil: Solimena, Michele. Paul Langerhans Institute Dresden; Alemania
dc.description.fil
Fil: Ermacora, Mario Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
dc.journal.title
Journal of Biological Chemistry (online)
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.RA119.007607
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1074/jbc.RA119.007607
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