It Takes Two to Tango: Regulation of G Proteins by Dimerization

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2009 May 9

PMID 19424291

Citations 146

Authors

Raphael Gasper

Simon Meyer

Katja Gotthardt

Minhajuddin Sirajuddin

Alfred Wittinghofer

Affiliations

Soon will be listed here.

Abstract

Guanine nucleotide-binding (G) proteins, which cycle between a GDP- and a GTP-bound conformation, are conventionally regulated by GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs), and function by interacting with effector proteins in the GTP-bound 'on' state. Here we present another class of G proteins that are regulated by homodimerization, which we would categorize as G proteins activated by nucleotide-dependent dimerization (GADs). This class includes proteins such as signal recognition particle (SRP), dynamin, septins and the newly discovered Roco protein Leu-rich repeat kinase 2 (LRRK2). We propose that the juxtaposition of the G domains of two monomers across the GTP-binding sites activates the biological function of these proteins and the GTPase reaction.

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References

Yim L, Martinez-Vicente M, Villarroya M, Aguado C, Knecht E, Armengod M . The GTPase activity and C-terminal cysteine of the Escherichia coli MnmE protein are essential for its tRNA modifying function. J Biol Chem. 2003; 278(31):28378-87. DOI: 10.1074/jbc.M301381200. View

Meyer S, Scrima A, Versees W, Wittinghofer A . Crystal structures of the conserved tRNA-modifying enzyme GidA: implications for its interaction with MnmE and substrate. J Mol Biol. 2008; 380(3):532-47. DOI: 10.1016/j.jmb.2008.04.072. View

Niemann H, Knetsch M, Scherer A, Manstein D, Kull F . Crystal structure of a dynamin GTPase domain in both nucleotide-free and GDP-bound forms. EMBO J. 2001; 20(21):5813-21. PMC: 125706. DOI: 10.1093/emboj/20.21.5813. View

Moser C, Mol O, Goody R, Sinning I . The signal recognition particle receptor of Escherichia coli (FtsY) has a nucleotide exchange factor built into the GTPase domain. Proc Natl Acad Sci U S A. 1997; 94(21):11339-44. PMC: 23460. DOI: 10.1073/pnas.94.21.11339. View

Yeh Y, Kesavulu M, Li H, Wu S, Sun Y, Konozy E . Dimerization is important for the GTPase activity of chloroplast translocon components atToc33 and psToc159. J Biol Chem. 2007; 282(18):13845-53. DOI: 10.1074/jbc.M608385200. View

Goldberg J . Structural and functional analysis of the ARF1-ARFGAP complex reveals a role for coatomer in GTP hydrolysis. Cell. 1999; 96(6):893-902. DOI: 10.1016/s0092-8674(00)80598-x. View

COLBY G, Wu M, Tzagoloff A . MTO1 codes for a mitochondrial protein required for respiration in paromomycin-resistant mutants of Saccharomyces cerevisiae. J Biol Chem. 1998; 273(43):27945-52. DOI: 10.1074/jbc.273.43.27945. View

Egea P, Stroud R, Walter P . Targeting proteins to membranes: structure of the signal recognition particle. Curr Opin Struct Biol. 2005; 15(2):213-20. DOI: 10.1016/j.sbi.2005.03.007. View

Vetter I, Wittinghofer A . The guanine nucleotide-binding switch in three dimensions. Science. 2001; 294(5545):1299-304. DOI: 10.1126/science.1062023. View

10.

Pan X, Eathiraj S, Munson M, Lambright D . TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism. Nature. 2006; 442(7100):303-6. DOI: 10.1038/nature04847. View

11.

Egea P, Shan S, Napetschnig J, Savage D, Walter P, Stroud R . Substrate twinning activates the signal recognition particle and its receptor. Nature. 2004; 427(6971):215-21. DOI: 10.1038/nature02250. View

12.

Koenig P, Oreb M, Hofle A, Kaltofen S, Rippe K, Sinning I . The GTPase cycle of the chloroplast import receptors Toc33/Toc34: implications from monomeric and dimeric structures. Structure. 2008; 16(4):585-96. DOI: 10.1016/j.str.2008.01.008. View

13.

Koenig P, Oreb M, Rippe K, Muhle-Goll C, Sinning I, Schleiff E . On the significance of Toc-GTPase homodimers. J Biol Chem. 2008; 283(34):23104-12. DOI: 10.1074/jbc.M710576200. View

14.

Oreb M, Tews I, Schleiff E . Policing Tic 'n' Toc, the doorway to chloroplasts. Trends Cell Biol. 2007; 18(1):19-27. DOI: 10.1016/j.tcb.2007.10.002. View

15.

Sirajuddin M, Farkasovsky M, Hauer F, Kuhlmann D, Macara I, Weyand M . Structural insight into filament formation by mammalian septins. Nature. 2007; 449(7160):311-5. DOI: 10.1038/nature06052. View

16.

Decoster E, Vassal A, Faye G . MSS1, a nuclear-encoded mitochondrial GTPase involved in the expression of COX1 subunit of cytochrome c oxidase. J Mol Biol. 1993; 232(1):79-88. DOI: 10.1006/jmbi.1993.1371. View

17.

Leipe D, Wolf Y, Koonin E, Aravind L . Classification and evolution of P-loop GTPases and related ATPases. J Mol Biol. 2002; 317(1):41-72. DOI: 10.1006/jmbi.2001.5378. View

18.

Bosgraaf L, van Haastert P . Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta. 2003; 1643(1-3):5-10. DOI: 10.1016/j.bbamcr.2003.08.008. View

19.

Ertel F, Mirus O, Bredemeier R, Moslavac S, Becker T, Schleiff E . The evolutionarily related beta-barrel polypeptide transporters from Pisum sativum and Nostoc PCC7120 contain two distinct functional domains. J Biol Chem. 2005; 280(31):28281-9. DOI: 10.1074/jbc.M503035200. View

20.

Smith M, Hiltbrunner A, Kessler F, Schnell D . The targeting of the atToc159 preprotein receptor to the chloroplast outer membrane is mediated by its GTPase domain and is regulated by GTP. J Cell Biol. 2002; 159(5):833-43. PMC: 2173378. DOI: 10.1083/jcb.200208017. View