| Structural highlights
2rmk is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | RAC1 (HUMAN), PKN1, PKN, PRK1, PRKCL1 (HUMAN) |
| Activity: | Protein kinase C, with EC number 2.7.11.13 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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Function
[RAC1_HUMAN] Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In glioma cells, promotes cell migration and invasion.[1] [2] [3] [4] [5] Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.[6] [7] [8] [9] [10] [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.[11] [12] [13] [14] [15] [16] [17] [18] [19]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Protein kinase C-related kinase 1 (PRK1 or PKN) is involved in regulation of the intermediate filaments of the actin cytoskeleton, as well as having effects on processes as diverse as mitotic timing and apoptosis. It is activated by interacting with the Rho family small G proteins and arachidonic acid or by caspase cleavage. We have previously shown that the HR1b of PRK1 binds exclusively to Rac1, whereas the HR1a domain binds to both Rac1 and RhoA. Here, we have determined the solution structure of the HR1b-Rac complex. We show that HR1b binds to the C-terminal end of the effector loop and switch 2 of Rac1. Comparison with the HR1a-RhoA structure shows that this part of the Rac1-HR1b interaction is homologous to one of the contact sites that HR1a makes with RhoA. The Rac1 used in this study included the C-terminal polybasic region, which is frequently omitted from structural studies, as well as the core G domain. The Rac1 C-terminal region reverses in direction to interact with residues in switch 2, and the polybasic region itself interacts with residues in HR1b. The interactions with HR1b do not prevent the polybasic region being available to contact the negatively charged membrane phospholipids, which is considered to be its primary role. This is the first structural demonstration that the C terminus of a G protein forms a novel recognition element for effector binding.
The Rac1 polybasic region is required for interaction with its effector PRK1.,Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HR J Biol Chem. 2008 Jan 18;283(3):1492-500. Epub 2007 Nov 15. PMID:18006505[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401-10. PMID:1643658
- ↑ Vincent S, Settleman J. The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization. Mol Cell Biol. 1997 Apr;17(4):2247-56. PMID:9121475
- ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
- ↑ Hamill KJ, Hopkinson SB, DeBiase P, Jones JC. BPAG1e maintains keratinocyte polarity through beta4 integrin-mediated modulation of Rac1 and cofilin activities. Mol Biol Cell. 2009 Jun;20(12):2954-62. doi: 10.1091/mbc.E09-01-0051. Epub 2009, Apr 29. PMID:19403692 doi:10.1091/mbc.E09-01-0051
- ↑ Li X, Lee AY. Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase. J Biol Chem. 2010 Oct 15;285(42):32436-45. doi: 10.1074/jbc.M110.120451. Epub, 2010 Aug 9. PMID:20696765 doi:10.1074/jbc.M110.120451
- ↑ Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401-10. PMID:1643658
- ↑ Vincent S, Settleman J. The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization. Mol Cell Biol. 1997 Apr;17(4):2247-56. PMID:9121475
- ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
- ↑ Hamill KJ, Hopkinson SB, DeBiase P, Jones JC. BPAG1e maintains keratinocyte polarity through beta4 integrin-mediated modulation of Rac1 and cofilin activities. Mol Biol Cell. 2009 Jun;20(12):2954-62. doi: 10.1091/mbc.E09-01-0051. Epub 2009, Apr 29. PMID:19403692 doi:10.1091/mbc.E09-01-0051
- ↑ Li X, Lee AY. Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase. J Biol Chem. 2010 Oct 15;285(42):32436-45. doi: 10.1074/jbc.M110.120451. Epub, 2010 Aug 9. PMID:20696765 doi:10.1074/jbc.M110.120451
- ↑ 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
- ↑ Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HR. The Rac1 polybasic region is required for interaction with its effector PRK1. J Biol Chem. 2008 Jan 18;283(3):1492-500. Epub 2007 Nov 15. PMID:18006505 doi:10.1074/jbc.M706760200
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