RGD Reference Report - The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-trisphosphate receptors and protects them from proteolytic cleavage.

General

The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-trisphosphate receptors and protects them from proteolytic cleavage.
Authors:	Schulman, JJ Wright, FA Kaufmann, T Wojcikiewicz, RJ
Citation:	Schulman JJ, etal., J Biol Chem. 2013 Aug 30;288(35):25340-9. doi: 10.1074/jbc.M113.496570. Epub 2013 Jul 24.
RGD ID:	11535097
Pubmed:	PMID:23884412 (View Abstract at PubMed)
PMCID:	PMC3757198 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M113.496570 (Journal Full-text)
Bok is a member of the Bcl-2 protein family that controls intrinsic apoptosis. Bok is most closely related to the pro-apoptotic proteins Bak and Bax, but in contrast to Bak and Bax, very little is known about its cellular role. Here we report that Bok binds strongly and constitutively to inositol 1,4,5-trisphosphate receptors (IP3Rs), proteins that form tetrameric calcium channels in the endoplasmic reticulum (ER) membrane and govern the release of ER calcium stores. Bok binds most strongly to IP3R1 and IP3R2, and barely to IP3R3, and essentially all cellular Bok is IP3R bound in cells that express substantial amounts of IP3Rs. Binding to IP3Rs appears to be mediated by the putative BH4 domain of Bok and the docking site localizes to a small region within the coupling domain of IP3Rs (amino acids 1895-1903 of IP3R1) that is adjacent to numerous regulatory sites, including sites for proteolysis. With regard to the possible role of Bok-IP3R binding, the following was observed: (i) Bok does not appear to control the ability of IP3Rs to release ER calcium stores, (ii) Bok regulates IP3R expression, (iii) persistent activation of inositol 1,4,5-trisphosphate-dependent cell signaling causes Bok degradation by the ubiquitin-proteasome pathway, in a manner that parallels IP3R degradation, and (iv) Bok protects IP3Rs from proteolysis, either by chymotrypsin in vitro or by caspase-3 in vivo during apoptosis. Overall, these data show that Bok binds strongly and constitutively to IP3Rs and that the most significant consequence of this binding appears to be protection of IP3Rs from proteolysis. Thus, Bok may govern IP3R cleavage and activity during apoptosis.

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Molecular Function

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
protein binding	enables	IPI	UniProtKB:O35425	11535097; 11535097	PMID:23884412	UniProt

Objects Annotated

Genes (Rattus norvegicus)

Itpr2 (inositol 1,4,5-trisphosphate receptor, type 2)

Itpr3 (inositol 1,4,5-trisphosphate receptor, type 3)

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The Bcl-2 protein family member Bok binds to the coupling domain of inositol 1,4,5-trisphosphate receptors and protects them from proteolytic cleavage.