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

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 stu...

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Autores principales: Torkko, Juha M, Primo, M. Evangelina, Dirkx, Ronald, Friedrich, Anne, Viehrig, Antje, Vergari, Elisa, Borgonovo, Barbara, Sönmez, Anke, Wegbrod, Carolin, Lachnit, Martina, Münster, Carla, Sica, Mauricio Pablo, Ermácora, Mario Roberto, Solimena, Michele
Formato: Articulo
Lenguaje:Inglés
Publicado: 2015
Materias:
Biología
Insulin
Protein tyrosine kinase
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/86902
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-86902
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Insulin
Protein tyrosine kinase
spellingShingle Biología
Insulin
Protein tyrosine kinase
Torkko, Juha M
Primo, M. Evangelina
Dirkx, Ronald
Friedrich, Anne
Viehrig, Antje
Vergari, Elisa
Borgonovo, Barbara
Sönmez, Anke
Wegbrod, Carolin
Lachnit, Martina
Münster, Carla
Sica, Mauricio Pablo
Ermácora, Mario Roberto
Solimena, Michele
Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
topic_facet Biología
Insulin
Protein tyrosine kinase
description 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.
format Articulo
Articulo
author Torkko, Juha M
Primo, M. Evangelina
Dirkx, Ronald
Friedrich, Anne
Viehrig, Antje
Vergari, Elisa
Borgonovo, Barbara
Sönmez, Anke
Wegbrod, Carolin
Lachnit, Martina
Münster, Carla
Sica, Mauricio Pablo
Ermácora, Mario Roberto
Solimena, Michele
author_facet Torkko, Juha M
Primo, M. Evangelina
Dirkx, Ronald
Friedrich, Anne
Viehrig, Antje
Vergari, Elisa
Borgonovo, Barbara
Sönmez, Anke
Wegbrod, Carolin
Lachnit, Martina
Münster, Carla
Sica, Mauricio Pablo
Ermácora, Mario Roberto
Solimena, Michele
author_sort Torkko, Juha M
title Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
title_short Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
title_full Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
title_fullStr Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
title_full_unstemmed Stability of proICA512/IA-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
title_sort stability of proica512/ia-2 and its targeting to insulin secretory granules require β4-sheet-mediated dimerization of its ectodomain in the endoplasmic reticulum
publishDate 2015
url http://sedici.unlp.edu.ar/handle/10915/86902
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