| Structural highlights
4nkg is a 4 chain structure with sequence from Human and Salt1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 4nkh |
| Gene: | sspH1, STM14_1483 (SALT1), PAK1, PKN, PKN1, PRK1, PRKCL1 (HUMAN) |
| Activity: | Protein kinase C, with EC number 2.7.11.13 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[SSPH1_SALT1] Effector proteins function to alter host cell physiology and promote bacterial survival in host tissues. This protein is an E3 ubiquitin ligase that interferes with host's ubiquitination pathway. Can ubiquitinate both ubiquitin and host PKN1. Down-modulates production of host proinflammatory cytokines by inhibiting NF-kappa-B-dependent gene expression, probably via interaction with PKN1.[1] [2] [3] [4] [PKN1_HUMAN] PKC-related serine/threonine-protein kinase involved in various processes such as regulation of the intermediate filaments of the actin cytoskeleton, cell migration, tumor cell invasion and transcription regulation. Regulates the cytoskeletal network by phosphorylating proteins such as VIM and neurofilament proteins NEFH, NEFL and NEFM, leading to inhibit their polymerization. Phosphorylates 'Ser-575', 'Ser-637' and 'Ser-669' of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly. Acts as a key coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-11' of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 'Lys-9' (H3K9me) by KDM4C/JMJD2C. Phosphorylates HDAC5, HDAC7 and HDAC9, leading to impair their import in the nucleus. Phosphorylates 'Thr-38' of PPP1R14A, 'Ser-159', 'Ser-163' and 'Ser-170' of MARCKS, and GFAP. Able to phosphorylate RPS6 in vitro.[5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
IpaH proteins are bacterial-specific E3 enzymes that function as T3SS effectors in Salmonella, Shigella, and other gram-negative bacteria. IpaH enzymes recruit host substrates for ubiquitination via an LRR domain, which can inhibit the catalytic domain in the absence of substrate. The basis for substrate recognition and the alleviation of autoinhibition upon substrate binding is unknown. Here we report the X-ray structure of Salmonella SspH1 in complex with human PKN1. The LRR domain of SspH1 interacts specifically with the HR1b coiled-coil sub-domain of PKN1 in manner that sterically displaces the catalytic domain from the LRR domain, and thereby activates catalytic function. SspH1 catalyzes the ubiquitination and proteasome-dependent degradation of PKN1 in cells, which attenuates androgen receptor responsiveness but not NF-kappaB activity. These regulatory features are conserved in other IpaH-substrate interactions. Our results explain the mechanism whereby substrate recognition and enzyme autoregulation are coupled in this class of bacterial effector proteins.
Structure of an SspH1-PKN1 complex reveals the basis for host substrate recognition and mechanism of activation for a bacterial E3 ubiquitin ligase.,Keszei AF, Tang X, McCormick C, Zeqiraj E, Rohde JR, Tyers M, Sicheri F Mol Cell Biol. 2013 Nov 18. PMID:24248594[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Miao EA, Scherer CA, Tsolis RM, Kingsley RA, Adams LG, Baumler AJ, Miller SI. Salmonella typhimurium leucine-rich repeat proteins are targeted to the SPI1 and SPI2 type III secretion systems. Mol Microbiol. 1999 Nov;34(4):850-64. PMID:10564523
- ↑ Haraga A, Miller SI. A Salmonella enterica serovar typhimurium translocated leucine-rich repeat effector protein inhibits NF-kappa B-dependent gene expression. Infect Immun. 2003 Jul;71(7):4052-8. PMID:12819095
- ↑ Haraga A, Miller SI. A Salmonella type III secretion effector interacts with the mammalian serine/threonine protein kinase PKN1. Cell Microbiol. 2006 May;8(5):837-46. PMID:16611232 doi:http://dx.doi.org/10.1111/j.1462-5822.2005.00670.x
- ↑ Rohde JR, Breitkreutz A, Chenal A, Sansonetti PJ, Parsot C. Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. Cell Host Microbe. 2007 Mar 15;1(1):77-83. PMID:18005683 doi:10.1016/j.chom.2007.02.002
- ↑ Palmer RH, Schonwasser DC, Rahman D, Pappin DJ, Herget T, Parker PJ. PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. FEBS Lett. 1996 Jan 15;378(3):281-5. PMID:8557118
- ↑ Mukai H, Toshimori M, Shibata H, Kitagawa M, Shimakawa M, Miyahara M, Sunakawa H, Ono Y. PKN associates and phosphorylates the head-rod domain of neurofilament protein. J Biol Chem. 1996 Apr 19;271(16):9816-22. PMID:8621664
- ↑ Matsuzawa K, Kosako H, Inagaki N, Shibata H, Mukai H, Ono Y, Amano M, Kaibuchi K, Matsuura Y, Azuma I, Inagaki M. Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN. Biochem Biophys Res Commun. 1997 May 29;234(3):621-5. PMID:9175763 doi:http://dx.doi.org/10.1006/bbrc.1997.6669
- ↑ Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C. Phosphorylation of tau is regulated by PKN. J Biol Chem. 2001 Mar 30;276(13):10025-31. Epub 2000 Dec 4. PMID:11104762 doi:http://dx.doi.org/10.1074/jbc.M007427200
- ↑ Metzger E, Muller JM, Ferrari S, Buettner R, Schule R. A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer. EMBO J. 2003 Jan 15;22(2):270-80. PMID:12514133 doi:http://dx.doi.org/10.1093/emboj/cdg023
- ↑ Schmidt A, Durgan J, Magalhaes A, Hall A. Rho GTPases regulate PRK2/PKN2 to control entry into mitosis and exit from cytokinesis. EMBO J. 2007 Mar 21;26(6):1624-36. Epub 2007 Mar 1. PMID:17332740 doi:http://dx.doi.org/10.1038/sj.emboj.7601637
- ↑ Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JM, Potier N, Scheidtmann KH, Buettner R, Schule R. Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation. Nat Cell Biol. 2008 Jan;10(1):53-60. Epub 2007 Dec 9. PMID:18066052 doi:http://dx.doi.org/10.1038/ncb1668
- ↑ Harrison BC, Huynh K, Lundgaard GL, Helmke SM, Perryman MB, McKinsey TA. Protein kinase C-related kinase targets nuclear localization signals in a subset of class IIa histone deacetylases. FEBS Lett. 2010 Mar 19;584(6):1103-10. doi: 10.1016/j.febslet.2010.02.057. Epub, 2010 Feb 24. PMID:20188095 doi:http://dx.doi.org/10.1016/j.febslet.2010.02.057
- ↑ Lachmann S, Jevons A, De Rycker M, Casamassima A, Radtke S, Collazos A, Parker PJ. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration. PLoS One. 2011;6(7):e21732. doi: 10.1371/journal.pone.0021732. Epub 2011 Jul 6. PMID:21754995 doi:http://dx.doi.org/10.1371/journal.pone.0021732
- ↑ Keszei AF, Tang X, McCormick C, Zeqiraj E, Rohde JR, Tyers M, Sicheri F. Structure of an SspH1-PKN1 complex reveals the basis for host substrate recognition and mechanism of activation for a bacterial E3 ubiquitin ligase. Mol Cell Biol. 2013 Nov 18. PMID:24248594 doi:http://dx.doi.org/10.1128/MCB.01360-13
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