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Torkko, J.M.* ; Primo, M.E.* ; Dirk, R.* ; Friedrich, A.* ; Viehrig, A.* ; Vergari, E.* ; Borgonovo, B.* ; Sönmez, A.* ; Wegbrod, C.* ; Lachnit, M.* ; Münster, C.* ; Sica, M.P.* ; Ermácora, M.R.* ; Solimena, M.*

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

Mol. Cell. Biol. 35, 914-927 (2015)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The type-1 diabetes autoantigen ICA512/IA-2/RPTPN is a receptor protein tyrosine phosphatase of the insulin secretory granules, which regulates the size of granule stores, possibly via cleavage/signaling of its cytosolic tail. The role of its extracellular region, instead, 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 or N506A/G553D double mutants dimerize, but remain in the endoplasmic reticulum. Removal of the N-terminal fragment (ICA512-NTF) preceding ME ICA512 allows instead 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Protein-tyrosine Phosphatases; Tryptic Fragments; O-glycosylation; Cell-surface; Islet Cells; Beta-cells; Sea Module; Ica512; Ia-2; Cleavage
ISSN (print) / ISBN 0270-7306
e-ISSN 1098-5549
Zeitschrift Molecular and Cellular Biology
Quellenangaben Band: 35, Heft: 6, Seiten: 914-927 Artikelnummer: , Supplement: ,
Verlag American Society for Microbiology (ASM)
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)