Stability and targeting of proICA512/IA-2 to insulin secretory granules requires β4-sheet mediated dimerization of its ectodomain in the endoplasmic reticulum
| cic.isFulltext | true | es |
| cic.isPeerReviewed | true | es |
| cic.lugarDesarrollo | Instituto Multidisciplinario de Biología Celular | es |
| cic.version | info:eu-repo/semantics/acceptedVersion | es |
| dc.date.accessioned | 2016-06-21T18:01:22Z | |
| dc.date.available | 2016-06-21T18:01:22Z | |
| dc.identifier.uri | https://digital.cic.gba.gob.ar/handle/11746/2283 | |
| dc.title | Stability and targeting of proICA512/IA-2 to insulin secretory granules requires β4-sheet mediated dimerization of its ectodomain in the endoplasmic reticulum | en |
| dc.type | Artículo | es |
| dcterms.abstract | The 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. | en |
| dcterms.creator.author | Torkko, Juha M. | es |
| dcterms.creator.author | Primo, María Evangelina | es |
| dcterms.creator.author | Dirkx, Ronald | es |
| dcterms.creator.author | Friedrich, Anne | es |
| dcterms.creator.author | Viehrig, Antje | es |
| dcterms.creator.author | Vergari, Elisa | es |
| dcterms.creator.author | Borgonovo, Bárbara | es |
| dcterms.creator.author | Sönmez, Anke | es |
| dcterms.creator.author | Wegbrod, Carolin | es |
| dcterms.creator.author | Lachnit, Martina | es |
| dcterms.creator.author | Münster, Carla | es |
| dcterms.creator.author | Sica, Mauricio | es |
| dcterms.creator.author | Ermácora, Mario | es |
| dcterms.creator.author | Solimena, Michele | es |
| dcterms.extent | p. 914-927 | es |
| dcterms.identifier.other | DOI 10.1128/MCB.00994-14 | es |
| dcterms.identifier.url | Documento completo | es |
| dcterms.isPartOf.issue | vol. 35, nº 6 | es |
| dcterms.isPartOf.series | Molecular and Cellular Biology | es |
| dcterms.issued | 2015-03 | |
| dcterms.language | Inglés | es |
| dcterms.license | Attribution 4.0 International (BY 4.0) | es |
| dcterms.publisher | American Society for Microbiology | es |
| dcterms.subject | diabetes | es |
| dcterms.subject | Insulina | es |
| dcterms.subject.materia | Biología Celular, Microbiología | es |
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