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5c2k

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Crystal structure of the fusion protein linked by RhoA and the GAP domain of MgcRacGAPCrystal structure of the fusion protein linked by RhoA and the GAP domain of MgcRacGAP

Structural highlights

5c2k is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.42Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RHOA_HUMAN Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague, and Yersinia pseudotuberculosis, which causes gastrointestinal disorders. Stimulates PKN2 kinase activity. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization.[1] [2] [3] [4] [5] [6] [7] [8] RGAP1_HUMAN Component of the centralspindlin complex that serves as a microtubule-dependent and Rho-mediated signaling required for the myosin contractile ring formation during the cell cycle cytokinesis. Plays key roles in controlling cell growth and differentiation of hematopoietic cells through mechanisms other than regulating Rac GTPase activity. Also involved in the regulation of growth-related processes in adipocytes and myoblasts. May be involved in regulating spermatogenesis and in the RACGAP1 pathway in neuronal proliferation. Shows strong GAP (GTPase activation) activity towards CDC42 and RAC1 and less towards RHOA. Essential for the early stages of embryogenesis. May play a role in regulating cortical activity through RHOA during cytokinesis. May participate in the regulation of sulfate transport in male germ cells.[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

Publication Abstract from PubMed

MgcRacGAP is a GTPase-activating protein (GAP) for the Rho family GTPases. During cytokinesis, MgcRacGAP localizes to the midbody, where it activates the GTPase activity of Rho family GTPases to facilitate cytokinesis. In the midbody, Aurora B phosphorylates Ser387 within the GAP domain of human MgcRacGAP, a modification that is suggested to influence GTPase preference. However, there are conflicting reports, with some studies indicating that Ser387 phosphorylation does not alter the GTPase preference of MgcRacGAP. This controversy highlights the need for a deeper understanding of the molecular interactions involved, which can be clarified through structural analyses. In the present study, we determined the crystal structures of the wild-type MgcRacGAP GAP domain complexed with CDC42*GDP*AlF(4)(-) and the S378D phosphomimetic mutant GAP domain fused with RHOA*GDP*AlF(4)(-). Additionally, crystal structures of the GAP domains were determined for the S387D and S387A mutants. Our analysis revealed that neither GTPase binding nor S387D mutation affected the overall structure of the GAP domain. However, comparison of the CDC42*MgcRacGAP (wild-type) complex with the RHOA-MgcRacGAP(S378D) fusion protein structure indicated that the S387D mutation caused positional shifts in both CDC42 and RHOA relative to MgcRacGAP. These shifts reduced interactions with CDC42 more severely than those with RHOA. In fact, the S387D mutation decreased the GTPase-activating activity of MgcRacGAP toward CDC42, while its impact on RHOA was only moderate. This difference in the rate of activity reduction may play an important role in GTPase preference.

Structural basis for the effects of Ser387 phosphorylation of MgcRacGAP on its GTPase-activating activities for CDC42 and RHOA.,Murayama K, Kato-Murayama M, Hosaka T, Kitamura T, Yokoyama S, Shirouzu M J Struct Biol. 2024 Nov 9;216(4):108151. doi: 10.1016/j.jsb.2024.108151. PMID:39522789[21]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ. Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling. J Biol Chem. 1996 Nov 15;271(46):28772-6. PMID:8910519
  2. ↑ 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
  3. ↑ Wing MR, Snyder JT, Sondek J, Harden TK. Direct activation of phospholipase C-epsilon by Rho. J Biol Chem. 2003 Oct 17;278(42):41253-8. Epub 2003 Aug 4. PMID:12900402 doi:http://dx.doi.org/10.1074/jbc.M306904200
  4. ↑ Yuce O, Piekny A, Glotzer M. An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 2005 Aug 15;170(4):571-82. PMID:16103226 doi:10.1083/jcb.200501097
  5. ↑ Kamijo K, Ohara N, Abe M, Uchimura T, Hosoya H, Lee JS, Miki T. Dissecting the role of Rho-mediated signaling in contractile ring formation. Mol Biol Cell. 2006 Jan;17(1):43-55. Epub 2005 Oct 19. PMID:16236794 doi:10.1091/mbc.E05-06-0569
  6. ↑ 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
  7. ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
  8. ↑ Wallace SW, Magalhaes A, Hall A. The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells. Mol Cell Biol. 2011 Jan;31(1):81-91. doi: 10.1128/MCB.01001-10. Epub 2010 Oct 25. PMID:20974804 doi:10.1128/MCB.01001-10
  9. ↑ Kawashima T, Hirose K, Satoh T, Kaneko A, Ikeda Y, Kaziro Y, Nosaka T, Kitamura T. MgcRacGAP is involved in the control of growth and differentiation of hematopoietic cells. Blood. 2000 Sep 15;96(6):2116-24. PMID:10979956
  10. ↑ Toure A, Dorseuil O, Morin L, Timmons P, Jegou B, Reibel L, Gacon G. MgcRacGAP, a new human GTPase-activating protein for Rac and Cdc42 similar to Drosophila rotundRacGAP gene product, is expressed in male germ cells. J Biol Chem. 1998 Mar 13;273(11):6019-23. PMID:9497316
  11. ↑ Hirose K, Kawashima T, Iwamoto I, Nosaka T, Kitamura T. MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody. J Biol Chem. 2001 Feb 23;276(8):5821-8. Epub 2000 Nov 20. PMID:11085985 doi:http://dx.doi.org/10.1074/jbc.M007252200
  12. ↑ Toure A, Morin L, Pineau C, Becq F, Dorseuil O, Gacon G. Tat1, a novel sulfate transporter specifically expressed in human male germ cells and potentially linked to rhogtpase signaling. J Biol Chem. 2001 Jun 8;276(23):20309-15. Epub 2001 Mar 5. PMID:11278976 doi:http://dx.doi.org/10.1074/jbc.M011740200
  13. ↑ Mishima M, Kaitna S, Glotzer M. Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity. Dev Cell. 2002 Jan;2(1):41-54. PMID:11782313
  14. ↑ Lee JS, Kamijo K, Ohara N, Kitamura T, Miki T. MgcRacGAP regulates cortical activity through RhoA during cytokinesis. Exp Cell Res. 2004 Feb 15;293(2):275-82. PMID:14729465
  15. ↑ 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
  16. ↑ Yuce O, Piekny A, Glotzer M. An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 2005 Aug 15;170(4):571-82. PMID:16103226 doi:10.1083/jcb.200501097
  17. ↑ Zhao WM, Fang G. MgcRacGAP controls the assembly of the contractile ring and the initiation of cytokinesis. Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13158-63. Epub 2005 Aug 29. PMID:16129829 doi:http://dx.doi.org/0504145102
  18. ↑ Kamijo K, Ohara N, Abe M, Uchimura T, Hosoya H, Lee JS, Miki T. Dissecting the role of Rho-mediated signaling in contractile ring formation. Mol Biol Cell. 2006 Jan;17(1):43-55. Epub 2005 Oct 19. PMID:16236794 doi:10.1091/mbc.E05-06-0569
  19. ↑ Burkard ME, Maciejowski J, Rodriguez-Bravo V, Repka M, Lowery DM, Clauser KR, Zhang C, Shokat KM, Carr SA, Yaffe MB, Jallepalli PV. Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells. PLoS Biol. 2009 May 5;7(5):e1000111. doi: 10.1371/journal.pbio.1000111. Epub 2009, May 26. PMID:19468302 doi:10.1371/journal.pbio.1000111
  20. ↑ Wolfe BA, Takaki T, Petronczki M, Glotzer M. Polo-like kinase 1 directs assembly of the HsCyk-4 RhoGAP/Ect2 RhoGEF complex to initiate cleavage furrow formation. PLoS Biol. 2009 May 5;7(5):e1000110. doi: 10.1371/journal.pbio.1000110. Epub 2009, May 26. PMID:19468300 doi:10.1371/journal.pbio.1000110
  21. ↑ Murayama K, Kato-Murayama M, Hosaka T, Kitamura T, Yokoyama S, Shirouzu M. Structural basis for the effects of Ser387 phosphorylation of MgcRacGAP on its GTPase-activating activities for CDC42 and RHOA. J Struct Biol. 2024 Nov 9;216(4):108151. PMID:39522789 doi:10.1016/j.jsb.2024.108151

5c2k, resolution 1.42Å

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