Artículo . Molecular and Cellular Biology ; vol. 35, nº 6

Stability and targeting of proICA512/IA-2 to insulin secretory granules requires β4-sheet mediated dimerization of its ectodomain in the endoplasmic reticulum

Torkko, Juha M. | Primo, María Evangelina | Dirkx, Ronald | Friedrich, Anne | Viehrig, Antje | Vergari, Elisa | Borgonovo, Bárbara | Sönmez, Anke | Wegbrod, Carolin | Lachnit, Martina | Münster, Carla | Sica, Mauricio | Ermácora, Mario | Solimena, Michele
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.
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.
  • Origin info: Instituto Multidisciplinario de Biología Celular
  • Publisher: American Society for Microbiology
  • Subject: Biología Celular, Microbiología
  • Keyword: diabetes | Insulina
  • Lenguage: Inglés
  • Extension: p. 914-927

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  • Date of availability: 21 de junio de 2016
  • Date of accession: 21 de junio de 2016
  • Date issued: marzo de 2015
  • Others identifiers: DOI 10.1128/MCB.00994-14
  • URL to resource: https://digital.cic.gba.gob.ar/handle/11746/2283
  • Licence: Attribution 4.0 International (BY 4.0)
http://creativecommons.org/licenses/by/4.0/
This work is published under license Creative Commons Attribution 4.0 International (BY 4.0)
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