| Structural highlights
Disease
[DNJC3_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[DNJC3_HUMAN] Involved in the unfolded protein response (UPR) during ER stress. Co-chaperone of HSPA8/HSC70, it stimulates its ATPase activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity.[1] [2] [3] [4]
Publication Abstract from PubMed
P58(IPK) is one of the endoplasmic reticulum- (ER-) localised DnaJ (ERdj) proteins which interact with the chaperone BiP, the mammalian ER ortholog of Hsp70, and are thought to contribute to the specificity and regulation of its diverse functions. P58(IPK), expression of which is upregulated in response to ER stress, has been suggested to act as a co-chaperone, binding un- or misfolded proteins and delivering them to BiP. In order to give further insights into the functions of P58(IPK), and the regulation of BiP by ERdj proteins, we have determined the crystal structure of human P58(IPK) to 3.0 A resolution using a combination of molecular replacement and single wavelength anomalous diffraction. The structure shows the human P58(IPK) monomer to have a very elongated overall shape. In addition to the conserved J domain, P58(IPK) contains nine N-terminal tetratricopeptide repeat motifs, divided into three subdomains of three motifs each. The J domain is attached to the C-terminal end via a flexible linker, and the structure shows the conserved Hsp70-binding histidine-proline-aspartate (HPD) motif to be situated on the very edge of the elongated protein, 100 A from the putative binding site for unfolded protein substrates. The residues that comprise the surface surrounding the HPD motif are highly conserved in P58(IPK) from other organisms but more varied between the human ERdj proteins, supporting the view that their regulation of different BiP functions is facilitated by differences in BiP-binding.
The crystal structure of the human co-chaperone p58.,Svard M, Biterova EI, Bourhis JM, Guy JE PLoS One. 2011;6(7):e22337. Epub 2011 Jul 25. PMID:21799829[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ van Huizen R, Martindale JL, Gorospe M, Holbrook NJ. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem. 2003 May 2;278(18):15558-64. Epub 2003 Feb 24. PMID:12601012 doi:https://dx.doi.org/10.1074/jbc.M212074200
- ↑ Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG. The P58 cellular inhibitor complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity. J Biol Chem. 1996 Jan 19;271(3):1702-7. PMID:8576172
- ↑ Gale M Jr, Blakely CM, Hopkins DA, Melville MW, Wambach M, Romano PR, Katze MG. Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK. Mol Cell Biol. 1998 Feb;18(2):859-71. PMID:9447982
- ↑ Melville MW, Tan SL, Wambach M, Song J, Morimoto RI, Katze MG. The cellular inhibitor of the PKR protein kinase, P58(IPK), is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity. J Biol Chem. 1999 Feb 5;274(6):3797-803. PMID:9920933
- ↑ Svard M, Biterova EI, Bourhis JM, Guy JE. The crystal structure of the human co-chaperone p58. PLoS One. 2011;6(7):e22337. Epub 2011 Jul 25. PMID:21799829 doi:10.1371/journal.pone.0022337
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