Crystal structure of RhoA–GDP and its functional implications

Wei, Yang; Zhang, Yan; Derewenda, Urszula; Liu, Xiaopu; Minor, Władek; Nakamoto, Robert K.; Somlyo, Avril V.; Somlyo, Andrew P.; Derewenda, Zygmunt S.

doi:10.1038/nsb0997-699

Cited by 179 publications

(150 citation statements)

References 30 publications

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“…In that study, the authors point out the unusual feature of the solvent exposed lipophilic amino (29). Switch I undergoes conformational changes during nucleotide exchange but the solvent accessibility of the side chain of Asn 41 does not change, as can be deduced from the crystal structures of Rho-GTP and Rho-GDP (27,30). The nucleotide-dependent time course of the ADP-ribosylation revealed that Rho-GDP is the optimal substrate and that binding of the GTP analogues Gpp(NH)p or GTP␥S decreases the rate of reaction by a factor of five but does not change the total amount of ADP-ribosylation.…”

Section: Discussionmentioning

confidence: 99%

Recognition of RhoA by Clostridium botulinum C3 Exoenzyme

Wilde

Genth

Aktories

et al. 2000

Journal of Biological Chemistry

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The C3-like ADP-ribosyltransferases exhibit a very confined substrate specificity compared with other Rhomodifying bacterial toxins; they selectively modify the RhoA, -B, and -C isoforms but not other members of the Rho or Ras subfamilies. In this study, the amino acid residues involved in the RhoA substrate recognition by C3 from Clostridium botulinum are identified by applying mutational analyses of the nonsubstrate Rac. First, the minimum domain responsible for the recognition by C3 was identified as the N-terminal 90 residues. Second, the combination of the N-terminal basic amino acids

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Section: Discussionmentioning

confidence: 99%

Recognition of RhoA by Clostridium botulinum C3 Exoenzyme

Wilde

Genth

Aktories

et al. 2000

Journal of Biological Chemistry

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“…Only the use of a dominant negative RhoA or inactivation of Rho by C3 exoenzyme could induce apoptosis in our studies. The switch 1 mutant RhoA A37 is likely functioning as a dominant negative in our studies because it cannot stabilize Mg 2+ chelation in its GTPbound form, thus favoring the GDP-bound inactive form (Wei et al, 1997). This might permit sequestration of Rho guanine nucleotide exchange factors from interacting with endogenous Rho protein.…”

Section: Discussionmentioning

confidence: 99%

A balance of signaling by Rho family small GTPases RhoA, Rac1 and Cdc42 coordinates cytoskeletal morphology but not cell survival

et al. 1999

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“…GS is composed of a catalytic subunit encoded by the two homologous genes FKS1 and FKS2 (Inoue et al, 1995;Mazur et al, 1995), and a regulatory subunit, the small GTPase, Rho1p (Drgonova et al, 1996;Qadota et al, 1996). The Rho-type GTPase is generally regulated by switching between a GDPbound inactive state and a GTP-bound active state (Wei et al, 1997;Ihara et al, 1998). Various factors are involved in the regulation of ␤-1,3-glucan synthesis by Rho1p in yeast cells.…”

Section: Discussionmentioning

confidence: 99%

Loss of Function ofKRE5Suppresses Temperature Sensitivity of Mutants Lacking Mitochondrial Anionic Lipids

Zhong

Gvozdenović-Jeremić

Webster

et al. 2005

MBoC

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Disruption of PGS1, which encodes the enzyme that catalyzes the committed step of cardiolipin (CL) synthesis, results in loss of the mitochondrial anionic phospholipids phosphatidylglycerol (PG) and CL. The pgs1⌬ mutant exhibits severe growth defects at 37°C. To understand the essential functions of mitochondrial anionic lipids at elevated temperatures, we isolated suppressors of pgs1⌬ that grew at 37°C. One of the suppressors has a loss of function mutation in KRE5, which is involved in cell wall biogenesis. The cell wall of pgs1⌬ contained markedly reduced ␤-1,3-glucan, which was restored in the suppressor. Stabilization of the cell wall with osmotic support alleviated the cell wall defects of pgs1⌬ and suppressed the temperature sensitivity of all CL-deficient mutants. Evidence is presented suggesting that the previously reported inability of pgs1⌬ to grow in the presence of ethidium bromide was due to defective cell wall integrity, not from "petite lethality." These findings demonstrated that mitochondrial anionic lipids are required for cellular functions that are essential in cell wall biogenesis, the maintenance of cell integrity, and survival at elevated temperature. INTRODUCTIONCardiolipin (CL), a unique anionic phospholipid with dimeric structure, is ubiquitous in eukaryotes and primarily found in the mitochondrial inner membrane . CL plays a key role in mitochondrial bioenergetics (Jiang et al., 2000; Greenberg, 2000, 2002;Schlame et al., 2000;Pfeiffer et al., 2003) and is also involved in mitochondrial biogenesis (Kawasaki et al., 1999;Jiang et al., 2000). Defective remodeling of CL is associated with Barth syndrome, a severe genetic disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, and respiratory chain defects (Vreken et al., 2000). The phenotype of Barth syndrome is dependent upon multiple factors that are not well understood (Barth et al., 1983(Barth et al., , 1996. Elucidation of the functions of CL will help to clarify the abnormalities associated with this disorder.The biosynthesis of CL is conserved in eukaryotic organisms. It occurs via three enzymatic reactions , including formation of phosphatidylglycerolphosphate (PGP) from CDP-DAG and glycerol-3-P, dephosphorylation of PGP to phosphatidylglycerol (PG), and condensation of CDP-DAG and PG to form CL. Disruption of PGS1, the structural gene encoding PGP synthase, results in the complete loss of both PG and CL (Janitor et al., 1996;Chang et al., 1998a). The crd1⌬ mutant, which lacks CL synthase, has no detectable CL but accumulates PG (Jiang et al., 1997;Chang et al., 1998b;Tuller et al., 1998;Jiang et al., 2000;Pfeiffer et al., 2003;Zhong et al., 2004). The human taffazin gene (TAZ1), which is associated with Barth syndrome, encodes a transacylase that may be involved in the remodeling of CL (Xu et al., 2003). Deletion of the yeast homolog of this gene, TAZ1, leads to decreased CL, aberrant CL acyl species, and accumulation of monolysocardiolipin . Mutants deficient in CL biosynthesis exhibit growth defects at elevat...

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Crystal structure of RhoA–GDP and its functional implications

Abstract: RhoA, a ubiquitous intracellular GTPase, mediates cytoskeletal responses to extracellular signals. A 2.1 A resolution crystal structure of the human RhoA-GDP complex shows unique stereochemistry in the switch I region, which results in a novel mode of Mg2+ binding.

Cited by 179 publications

References 30 publications

Recognition of RhoA by Clostridium botulinum C3 Exoenzyme

Recognition of RhoA by Clostridium botulinum C3 Exoenzyme

A balance of signaling by Rho family small GTPases RhoA, Rac1 and Cdc42 coordinates cytoskeletal morphology but not cell survival

Loss of Function ofKRE5Suppresses Temperature Sensitivity of Mutants Lacking Mitochondrial Anionic Lipids

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