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

Autores
Toledo, Pamela Ludmila; Torkko, Juha Markunpoika; Müller, Andreas; Wegbrod, Carolin; Sönmez, Anke; Solimena, Michele; Ermacora, Mario Roberto
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
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
Fil: Torkko, Juha Markunpoika. Paul Langerhans Institute Dresden; Alemania
Fil: Müller, Andreas. Paul Langerhans Institute Dresden; Alemania
Fil: Wegbrod, Carolin. Paul Langerhans Institute Dresden; Alemania
Fil: Sönmez, Anke. Paul Langerhans Institute Dresden; Alemania
Fil: Solimena, Michele. Paul Langerhans Institute Dresden; Alemania
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
Materia
IA-2
ICA512
PTPRN
aggregation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/128337
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/128337
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitorToledo, Pamela LudmilaTorkko, Juha MarkunpoikaMüller, AndreasWegbrod, CarolinSönmez, AnkeSolimena, MicheleErmacora, Mario RobertoIA-2ICA512PTPRNaggregationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Type 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.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; ArgentinaFil: Torkko, Juha Markunpoika. Paul Langerhans Institute Dresden; AlemaniaFil: Müller, Andreas. Paul Langerhans Institute Dresden; AlemaniaFil: Wegbrod, Carolin. Paul Langerhans Institute Dresden; AlemaniaFil: Sönmez, Anke. Paul Langerhans Institute Dresden; AlemaniaFil: Solimena, Michele. Paul Langerhans Institute Dresden; AlemaniaFil: 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; ArgentinaAmerican Society for Biochemistry and Molecular Biology2019-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/128337Toledo, 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; 8564-85760021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.RA119.007607info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA119.007607info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:37:36Zoai:ri.conicet.gov.ar:11336/128337instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:37:37.0CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor
title ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor
spellingShingle ICA512 RESP18 homology domain is a protein condensing factor and insulin fibrillation inhibitor
Toledo, Pamela Ludmila
IA-2
ICA512
PTPRN
aggregation
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
dc.creator.none.fl_str_mv Toledo, Pamela Ludmila
Torkko, Juha Markunpoika
Müller, Andreas
Wegbrod, Carolin
Sönmez, Anke
Solimena, Michele
Ermacora, Mario Roberto
author Toledo, Pamela Ludmila
author_facet Toledo, Pamela Ludmila
Torkko, Juha Markunpoika
Müller, Andreas
Wegbrod, Carolin
Sönmez, Anke
Solimena, Michele
Ermacora, Mario Roberto
author_role author
author2 Torkko, Juha Markunpoika
Müller, Andreas
Wegbrod, Carolin
Sönmez, Anke
Solimena, Michele
Ermacora, Mario Roberto
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv IA-2
ICA512
PTPRN
aggregation
topic IA-2
ICA512
PTPRN
aggregation
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
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
Fil: Torkko, Juha Markunpoika. Paul Langerhans Institute Dresden; Alemania
Fil: Müller, Andreas. Paul Langerhans Institute Dresden; Alemania
Fil: Wegbrod, Carolin. Paul Langerhans Institute Dresden; Alemania
Fil: Sönmez, Anke. Paul Langerhans Institute Dresden; Alemania
Fil: Solimena, Michele. Paul Langerhans Institute Dresden; Alemania
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
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 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.
publishDate 2019
dc.date.none.fl_str_mv 2019-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/128337
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
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/128337
identifier_str_mv 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
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jbc.org/lookup/doi/10.1074/jbc.RA119.007607
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA119.007607
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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