| Structural highlights
Function
[CDC42_HUMAN] Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase. Plays a role in the extension and maintenance of the formation of thin, actin-rich surface projections called filopodia. Mediates CDC42-dependent cell migration.[1] [2] [3] [PAK3_MOUSE] Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments.[4] [5] [6] [7]
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
Cdc42Hs is a member of the Ras superfamily of GTPases and initiates a cascade that begins with the activation of several kinases, including p21-activated kinase (PAK). We have previously used a 46 amino acid fragment of PAK (PBD46) to define the binding surface on Cdc42Hs [Guo et al. (1998) Biochemistry 37, 14030-14037]. Here we describe the three-dimensional solution structure of the Cdc42Hs. GMPPCP-PBD46 complex. Heteronuclear NMR methods were used to assign resonances in the complex, and approximately 2400 distance and dihedral restraints were used to calculate a set of 20 structures using a combination of distance geometry, simulated annealing, and chemical shift and Ramachandran refinement. The overall structure of Cdc42Hs in the complex differs from the uncomplexed structure in two major aspects: (1) the first alpha helix is reoriented to accommodate the binding of the peptide and (2) the regions corresponding to switch I and switch II are less disordered. As suggested by our previous work (Guo et al., 1998) and similar to the complex between Cdc42Hs and fACK [Mott et al. (1999) Nature 399, 384-388], PBD46 forms an intermolecular beta-sheet with beta2 of Cdc42Hs and contacts both switch I and switch II. The extensive binding surface between PBD46 and Cdc42Hs can account for both the high affinity of the complex and the inhibition by PBD46 of GTP hydrolysis.
Structure of the complex of Cdc42Hs with a peptide derived from P-21 activated kinase.,Gizachew D, Guo W, Chohan KK, Sutcliffe MJ, Oswald RE Biochemistry. 2000 Apr 11;39(14):3963-71. PMID:10747784[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gauthier-Campbell C, Bredt DS, Murphy TH, El-Husseini Ael-D. Regulation of dendritic branching and filopodia formation in hippocampal neurons by specific acylated protein motifs. Mol Biol Cell. 2004 May;15(5):2205-17. Epub 2004 Feb 20. PMID:14978216 doi:10.1091/mbc.E03-07-0493
- ↑ Oceguera-Yanez F, Kimura K, Yasuda S, Higashida C, Kitamura T, Hiraoka Y, Haraguchi T, Narumiya S. Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis. J Cell Biol. 2005 Jan 17;168(2):221-32. Epub 2005 Jan 10. PMID:15642749 doi:10.1083/jcb.200408085
- ↑ Modzelewska K, Newman LP, Desai R, Keely PJ. Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas. J Biol Chem. 2006 Dec 8;281(49):37527-35. Epub 2006 Oct 12. PMID:17038317 doi:10.1074/jbc.M604342200
- ↑ Buscemi N, Foster DB, Neverova I, Van Eyk JE. p21-activated kinase increases the calcium sensitivity of rat triton-skinned cardiac muscle fiber bundles via a mechanism potentially involving novel phosphorylation of troponin I. Circ Res. 2002 Sep 20;91(6):509-16. PMID:12242269
- ↑ Boda B, Alberi S, Nikonenko I, Node-Langlois R, Jourdain P, Moosmayer M, Parisi-Jourdain L, Muller D. The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. J Neurosci. 2004 Dec 1;24(48):10816-25. PMID:15574732 doi:http://dx.doi.org/24/48/10816
- ↑ Kreis P, Thevenot E, Rousseau V, Boda B, Muller D, Barnier JV. The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway. J Biol Chem. 2007 Jul 20;282(29):21497-506. Epub 2007 May 30. PMID:17537723 doi:http://dx.doi.org/10.1074/jbc.M703298200
- ↑ Ouyang Y, Mamidi R, Jayasundar JJ, Chandra M, Dong WJ. Structural and kinetic effects of PAK3 phosphorylation mimic of cTnI(S151E) on the cTnC-cTnI interaction in the cardiac thin filament. J Mol Biol. 2010 Jul 30;400(5):1036-45. doi: 10.1016/j.jmb.2010.06.007. Epub 2010, Jun 9. PMID:20540949 doi:http://dx.doi.org/10.1016/j.jmb.2010.06.007
- ↑ Gizachew D, Guo W, Chohan KK, Sutcliffe MJ, Oswald RE. Structure of the complex of Cdc42Hs with a peptide derived from P-21 activated kinase. Biochemistry. 2000 Apr 11;39(14):3963-71. PMID:10747784
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