Stability and targeting of proICA512/IA-2 to insulin secretory granules requires beta4-sheet mediated dimerization of its ectodomain in the endoplasmic reticulum

Página de ítem simple
cic.isFulltexttruees
cic.isPeerReviewedtruees
cic.lugarDesarrolloInstituto Multidisciplinario de Biología Celular es
cic.versioninfo:eu-repo/semantics/acceptedVersiones
dc.date.accessioned2016-09-15T11:53:45Z
dc.date.available2016-09-15T11:53:45Z
dc.identifier.urihttps://digital.cic.gba.gob.ar/handle/11746/4227
dc.titleStability and targeting of proICA512/IA-2 to insulin secretory granules requires beta4-sheet mediated dimerization of its ectodomain in the endoplasmic reticulumen
dc.typeArtículoes
dcterms.abstractThe type 1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules (SGs) which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region remains unknown. Structural studies indicated that β2- or β4-strands in the mature ectodomain (ME ICA512) form dimers in vitro. Here we show that ME ICA512 prompts proICA512 dimerization in the endoplasmic reticulum. Perturbation of ME ICA512 β2-strand N-glycosylation upon S508A replacement allows for proICA512 dimerization, O-glycosylation, targeting to granules, and conversion, which are instead precluded upon G553D replacement in the ME ICA512 β4-strand. S508A/G553D and N506A/G553D double mutants dimerize but remain in the endoplasmic reticulum. Removal of the N-terminal fragment (ICA512-NTF) preceding ME ICA512 allows an ICA512-ΔNTF G553D mutant to exit the endoplasmic reticulum, and ICA512-ΔNTF is constitutively delivered to the cell surface. The signal for SG sorting is located within the NTF RESP18 homology domain (RESP18-HD), whereas soluble NTF is retained in the endoplasmic reticulum. Hence, we propose that the ME ICA512 β2-strand fosters proICA512 dimerization until NTF prevents N506 glycosylation. Removal of this constraint allows for proICA512 β4-strand-induced dimerization, exit from the endoplasmic reticulum, O-glycosylation, and RESP18-HD-mediated targeting to granules.es
dcterms.creator.authorTorkko, J.es
dcterms.creator.authorPrimo, M.es
dcterms.creator.authorDirkx, R.es
dcterms.creator.authorFriedrich, A.es
dcterms.creator.authorViehrig, A.es
dcterms.creator.authorVergari, E.es
dcterms.creator.authorBorgonovo, B.es
dcterms.creator.authorSonmez, A.es
dcterms.creator.authorWegbrod, C.es
dcterms.creator.authorLachnit, M.es
dcterms.creator.authorMunster, C.es
dcterms.creator.authorSica, Mauricioes
dcterms.creator.authorEmárcora, M.es
dcterms.creator.authorSolimena, M.es
dcterms.extent49 p.es
dcterms.identifier.urlRecurso Completoes
dcterms.isPartOf.issuevol. 35es
dcterms.isPartOf.seriesMolecular and Cellular Biologyes
dcterms.issued2015
dcterms.languageIngléses
dcterms.licenseAttribution 4.0 International (BY 4.0)es
dcterms.subjecttype-1 diabetes autoantigen ICA512/IA-2/RPTPNen
dcterms.subjecttyrosine 30 phosphataseen
dcterms.subjectinsulin secretory granulesen
dcterms.subjectβ4- sheet mediated dimerizationen
dcterms.subjectectodomainen
dcterms.subjectendoplasmic reticulumen
dcterms.subject.materiaBiología Celular, Microbiologíaes

Archivos

Bloque original

Mostrando 1 - 1 de 1
Miniatura
Nombre:
Torkko Sica - Stability of proICA512 PDFA.pdf
Tamaño:
11.71 MB
Formato:
Adobe Portable Document Format
Descripción:
Documento completo
Descargar

Colecciones

Artículos y presentaciones en Congresos