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

Autores
Toledo, Pamela Ludmila; Vazquez, Diego Sebastian; Gianotti, Alejo Román; Abate, Milagros Belen; Wegbrod, Carolin; Torkko, Juha M.; Solimena, Michele; Ermacora, Mario Roberto
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
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: Vazquez, Diego Sebastian. 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: Gianotti, Alejo Román. 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: Abate, Milagros Belen. 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: Wegbrod, Carolin. Technische Universität Dresden.; Alemania
Fil: Torkko, Juha M.. Technische Universität Dresden.; Alemania
Fil: Solimena, Michele. Technische Universität 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
INSULIN
MESOSCOPIC CLUSTERS
NANOCONDENSATES
PROINSULIN
PROTEIN SECRETION
PROTEIN SORTING
PROTEIN TYROSINE PHOSPHATASE
PROTEIN–PROTEIN INTERACTIONS
SECRETORY GRANULE BIOGENESIS
Β CELL
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/227038
Acceder
id CONICETDig_e381f95fa87f7afd254b34659649c5e5
oai_identifier_str oai:ri.conicet.gov.ar:11336/227038
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domainToledo, Pamela LudmilaVazquez, Diego SebastianGianotti, Alejo RománAbate, Milagros BelenWegbrod, CarolinTorkko, Juha M.Solimena, MicheleErmacora, Mario RobertoINSULINMESOSCOPIC CLUSTERSNANOCONDENSATESPROINSULINPROTEIN SECRETIONPROTEIN SORTINGPROTEIN TYROSINE PHOSPHATASEPROTEIN–PROTEIN INTERACTIONSSECRETORY GRANULE BIOGENESISΒ CELLhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1ICA512/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.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: Vazquez, Diego Sebastian. 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: Gianotti, Alejo Román. 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: Abate, Milagros Belen. 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: Wegbrod, Carolin. Technische Universität Dresden.; AlemaniaFil: Torkko, Juha M.. Technische Universität Dresden.; AlemaniaFil: Solimena, Michele. Technische Universität 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; ArgentinaJohn Wiley & Sons2023-05info: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/11336/227038Toledo, Pamela Ludmila; Vazquez, Diego Sebastian; Gianotti, Alejo Román; Abate, Milagros Belen; Wegbrod, Carolin; et al.; Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain; John Wiley & Sons; Protein Science; 32; 6; 5-2023; 1-190961-8368CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/10.1002/pro.4649info:eu-repo/semantics/altIdentifier/doi/10.1002/pro.4649info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:23:21Zoai:ri.conicet.gov.ar:11336/227038instacron: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 10:23:21.356CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
title Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
spellingShingle Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
Toledo, Pamela Ludmila
INSULIN
MESOSCOPIC CLUSTERS
NANOCONDENSATES
PROINSULIN
PROTEIN SECRETION
PROTEIN SORTING
PROTEIN TYROSINE PHOSPHATASE
PROTEIN–PROTEIN INTERACTIONS
SECRETORY GRANULE BIOGENESIS
Β CELL
title_short Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
title_full Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
title_fullStr Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
title_full_unstemmed Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
title_sort Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain
dc.creator.none.fl_str_mv Toledo, Pamela Ludmila
Vazquez, Diego Sebastian
Gianotti, Alejo Román
Abate, Milagros Belen
Wegbrod, Carolin
Torkko, Juha M.
Solimena, Michele
Ermacora, Mario Roberto
author Toledo, Pamela Ludmila
author_facet Toledo, Pamela Ludmila
Vazquez, Diego Sebastian
Gianotti, Alejo Román
Abate, Milagros Belen
Wegbrod, Carolin
Torkko, Juha M.
Solimena, Michele
Ermacora, Mario Roberto
author_role author
author2 Vazquez, Diego Sebastian
Gianotti, Alejo Román
Abate, Milagros Belen
Wegbrod, Carolin
Torkko, Juha M.
Solimena, Michele
Ermacora, Mario Roberto
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv INSULIN
MESOSCOPIC CLUSTERS
NANOCONDENSATES
PROINSULIN
PROTEIN SECRETION
PROTEIN SORTING
PROTEIN TYROSINE PHOSPHATASE
PROTEIN–PROTEIN INTERACTIONS
SECRETORY GRANULE BIOGENESIS
Β CELL
topic INSULIN
MESOSCOPIC CLUSTERS
NANOCONDENSATES
PROINSULIN
PROTEIN SECRETION
PROTEIN SORTING
PROTEIN TYROSINE PHOSPHATASE
PROTEIN–PROTEIN INTERACTIONS
SECRETORY GRANULE BIOGENESIS
Β CELL
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
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: Vazquez, Diego Sebastian. 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: Gianotti, Alejo Román. 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: Abate, Milagros Belen. 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: Wegbrod, Carolin. Technische Universität Dresden.; Alemania
Fil: Torkko, Juha M.. Technische Universität Dresden.; Alemania
Fil: Solimena, Michele. Technische Universität 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 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.
publishDate 2023
dc.date.none.fl_str_mv 2023-05
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/11336/227038
Toledo, Pamela Ludmila; Vazquez, Diego Sebastian; Gianotti, Alejo Román; Abate, Milagros Belen; Wegbrod, Carolin; et al.; Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain; John Wiley & Sons; Protein Science; 32; 6; 5-2023; 1-19
0961-8368
CONICET Digital
CONICET
url http://hdl.handle.net/11336/227038
identifier_str_mv Toledo, Pamela Ludmila; Vazquez, Diego Sebastian; Gianotti, Alejo Román; Abate, Milagros Belen; Wegbrod, Carolin; et al.; Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain; John Wiley & Sons; Protein Science; 32; 6; 5-2023; 1-19
0961-8368
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/10.1002/pro.4649
info:eu-repo/semantics/altIdentifier/doi/10.1002/pro.4649
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
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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