Binding of Rac1, Rnd1, and RhoD to a Novel Rho GTPase Interaction Motif Destabilizes Dimerization of the Plexin-B1 Effector Domain

Plexins are the first known transmembrane receptors that interact directly with small GTPases. On binding to certain Rho family GTPases, the receptor regulates the remodeling of the actin cytoskeleton and alters cell movement in response to semaphorin guidance cues. In a joint solution NMR spectroscopy and x-ray crystallographic study, we characterize a 120-residue cytoplasmic independent folding domain of plexin-B1 that directly binds three Rho family GTPases, Rac1, Rnd1, and RhoD. The NMR data show that, surprisingly, the Cdc42/Rac interactive binding-like motif of plexin-B1 is not involved in this interaction. Instead, all three GTPases interact with the same region, β-strands 3 and 4 and a short α-helical segment of the plexin domain. The 2.0 Å resolution x-ray structure shows that these segments are brought together by the tertiary structure of the ubiquitin-like fold. In the crystal, the protein is dimerized with C2 symmetry through a four-stranded antiparallel β-sheet that is formed outside the fold by a long loop between the monomers. This region is adjacent to the GTPase binding motifs identified by NMR. Destabilization of the dimer in solution by binding of any one of the three GTPases suggests a model for receptor regulation that involves bidirectional signaling. The model implies a multifunctional role for the GTPase-plexin interaction that includes conformational change and a localization of active receptors in the signaling mechanism. Plexins are the first known transmembrane receptors that interact directly with small GTPases. On binding to certain Rho family GTPases, the receptor regulates the remodeling of the actin cytoskeleton and alters cell movement in response to semaphorin guidance cues. In a joint solution NMR spectroscopy and x-ray crystallographic study, we characterize a 120-residue cytoplasmic independent folding domain of plexin-B1 that directly binds three Rho family GTPases, Rac1, Rnd1, and RhoD. The NMR data show that, surprisingly, the Cdc42/Rac interactive binding-like motif of plexin-B1 is not involved in this interaction. Instead, all three GTPases interact with the same region, β-strands 3 and 4 and a short α-helical segment of the plexin domain. The 2.0 Å resolution x-ray structure shows that these segments are brought together by the tertiary structure of the ubiquitin-like fold. In the crystal, the protein is dimerized with C2 symmetry through a four-stranded antiparallel β-sheet that is formed outside the fold by a long loop between the monomers. This region is adjacent to the GTPase binding motifs identified by NMR. Destabilization of the dimer in solution by binding of any one of the three GTPases suggests a model for receptor regulation that involves bidirectional signaling. The model implies a multifunctional role for the GTPase-plexin interaction that includes conformational change and a localization of active receptors in the signaling mechanism. Members of the plexin family of transmembrane receptors have important functions in guiding axon growth in the developing nervous system (1Negishi M. Oinuma I. Katoh H. Cell. Mol. Life Sci. 2005; 62: 1363-1371Crossref PubMed Scopus (117) Google Scholar, 2Patel B.N. Van Vactor D.L. Curr. Opin. Cell Biol. 2002; 14: 221-229Crossref PubMed Scopus (64) Google Scholar, 3Artigiani S. Comoglio P.M. Tamagnone L. IUBMB Life. 1999; 48: 477-482Crossref PubMed Google Scholar). Plexins also function in several developmental processes such as cardiovascular development and angiogenesis (4Toyofuku T. Zhang H. Kumanogoh A. Takegahara N. Suto F. Kamei J. Aoki K. 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Cell Biol. 2002; 4: 720-724Crossref PubMed Scopus (364) Google Scholar), and in the immune system (10Wong A.W. Brickey W.J. Taxman D.J. van Deventer H.W. Reed W. Gao J.X. Zheng P. Liu Y. Li P. Blum J.S. McKinnon K.P. Ting J.P. Nat. Immunol. 2003; 4: 891-898Crossref PubMed Scopus (122) Google Scholar). The extracellular part of plexin shares significant homology with that of the hepatocyte growth factor receptor as well as with semaphorins, the principal family of ligands for plexins. The cytoplasmic region of plexins is also well conserved (11Tamagnone L. Artigiani S. Chen H. He Z. Ming G.I. Song H. Chedotal A. Winberg M.L. Goodman C.S. Poo M. Tessier-Lavigne M. Comoglio P.M. Cell. 1999; 99: 71-80Abstract Full Text Full Text PDF PubMed Scopus (950) Google Scholar). Two segments with homology to Ras GTPase-activating proteins (GAPs) 5The abbreviations used are:GAPGTPase-activating proteinRBDRho GTPase binding domainCRIBCdc42/Rac interactive bindingHSQCheteronuclear single quantum coherenceITCisothermal titration calorimetryTROSYtransverse relaxation optimized spectroscopyGMPPNPguanosine-5′-[(β,γ)-imido]triphosphateMTSL(1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-methyl)methanesulfonate. are linked by a region that has been identified as the location for the binding of several Rho family GTPases. GTPase-activating protein Rho GTPase binding domain Cdc42/Rac interactive binding heteronuclear single quantum coherence isothermal titration calorimetry transverse relaxation optimized spectroscopy guanosine-5′-[(β,γ)-imido]triphosphate (1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-methyl)methanesulfonate. Plexins are unique in that they are the first documented example of a transmembrane receptor that interacts directly with small GTPases. Most A- and B-family plexins bind activated Rac1 and Rnd1 (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar, H. A. I. Goodman C.S. A. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Goodman C.S. Full Text Full Text PDF PubMed Scopus Google Scholar, I. Puschel A.W. PubMed Scopus Google Scholar), Rho family GTPases that are known of and cell A. J. Cell Biol. 1999; PubMed Scopus Google Scholar). has also been to bind active I. Puschel A.W. J. 2002; PubMed Google Scholar), Rho family GTPase involved in actin remodeling and and in receptor Cell Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The role of these GTPase has as have the of the binding the Rho GTPase binding segment a GTPase to a by certain Rho family GTPases, as protein in response to GTPase binding H.G. Li W. Guan K.L. Genes Dev. 2002; PubMed Scopus Google Scholar, I. Y. Katoh H. M. 2004; PubMed Scopus Google Scholar, I. Katoh H. M. J. 2004; PubMed Scopus Google Scholar, S. J. Cell Biol. 2004; PubMed Scopus Google Scholar, I. Katoh H. A. M. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google is not certain Rac1, Rnd1, and bind to the same to of plexin and such binding is binding of one GTPase a conformational change in the binding of the Rho GTPase family J. Guan K.L. Nat. Mol. Cell Biol. 2005; PubMed Scopus Google Scholar). Rac1 and Rnd1 binding are known to the of and of the cytoplasmic plexin region I. Y. Katoh H. M. 2004; PubMed Scopus Google Scholar, I. Katoh H. M. J. 2004; PubMed Scopus Google Scholar, S. A. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), in the Rho GTPase binding region are involved in this has not been that a of the Rho GTPase binding segment a in of the signaling of The Rho GTPase binding region of plexins has been to that the (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar, H. A. I. Goodman C.S. A. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Goodman C.S. Full Text Full Text PDF PubMed Scopus Google Scholar, I. Puschel A.W. J. 2002; PubMed Google Scholar, I. Y. Katoh H. M. 2004; PubMed Scopus Google Scholar), the involved in binding have not been the of NMR for the region of plexin-B1 Y. M. J. NMR. 2005; PubMed Scopus Google as well as for active Rac1 S. M. J. NMR. PubMed Scopus Google Scholar). we of the GTPase-plexin interaction by solution NMR for the localization of the binding and of conformational that the interaction. also the x-ray structure of the plexin-B1 to this the ubiquitin-like fold of the is that the Rho GTPase binding is adjacent to the is by all three Rho GTPases in the multifunctional role of the Rho GTPase-plexin interaction and for Rho GTPase signaling in guidance and of the cytoplasmic region of plexin-B1 and a of used for the of and is to as Rho GTPase binding domain Two to in also for used to and proteins in cells in The with of and for NMR in with as the by growth in and in with cells in a 4 4 and and 4 as D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). used for in to plexin-B1 a of Rac1 proteins by a Rnd1 and protein by of protein by for GTPases with the in the of and show that the active of the GTPases to the Rac1 and Rnd1 used in of the and the of of protein solution and of a solution a of of growth used the of and protein are and the with a loop and in data the in data the structure in by the single PubMed Scopus Google with the Biol. 2002; PubMed Scopus Google Scholar), and model by the 2003; PubMed Scopus Google Scholar). data with the Biol. PubMed Scopus Google Scholar), J.S. Res. 2004; PubMed Scopus Google Scholar), and P. K. Biol. 2004; PubMed Scopus Google Scholar). data and model is in The crystallographic model of the in the with for x-ray structure of of by of by of J.S. 2003; PubMed Scopus Google Scholar). in a NMR in with between Rac1 Rnd1, with the solution a GTPase and in to a solution to for between Rac1 and the plexin and of protein of plexin-B1 a of Rac1 and plexin of and NMR Most of the of the and plexin-B1 by with of the protein and of the protein with Rac1 of the in the region of plexin by and The of and H. T. K. Y. I. Nat. Biol. 7: PubMed Scopus Google used to between Rac1 and plexin in and in of The in the the are to in I. 2005; PubMed Scopus Google Scholar). for as G. PubMed Scopus Google Scholar). Two used for the NMR a with one of the single proteins by the of the relaxation to this the by of the proteins with of with and with by of the and for the and motif of plexin-B1 and isothermal titration the proteins the same to the The the cell and the a the cell The of and the of plexin-B1 the GTPases. with in the cell of the GTPases. The data the is to in the of the GTPase-plexin The three The for for with the of proteins is as is the is the and is the to this between and of in the is the Rho GTPase protein of plexin-B1 of the segment that is between with homology to and that is known to bind active Rac1 and Rnd1 (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar, H. A. I. Goodman C.S. A. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, H.G. Li W. Guan K.L. Genes Dev. 2002; PubMed Scopus Google Scholar). binds to region of I. Puschel A.W. J. 2002; PubMed Google Scholar). The of as a of that well and segments of the The of the are by of the protein to that this region includes a domain and that the and in are of to as the Rho GTPase binding domain is the independent folding the in the the protein The plexin-B1 binds Rac1 in a the active Rac1 active not the of Rac1, bind plexin-B1 as by In we that the of plexin-B1 is by of that the plexin is for the activated are with and active RhoD. of the of and the crystallographic protein structure of the plexin-B1 the of the data and The structure is with the of the plexin-B1 as a fold Y. M. J. NMR. 2005; PubMed Scopus Google Scholar). The structure has a of Å for of and a of significant by the L. J. PubMed Scopus Google Scholar). In to the structure of this several long are in the and a shows α-helical is the of a short four-stranded antiparallel β-sheet is formed outside of the ubiquitin-like fold by the of loop The dimer has C2 and the that is for D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), is a The structure is by and the interaction of the with a and of the loop is in the any with this loop region in NMR D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). in as well as of to the region in a single structure in the that the well of the dimer is to the the of the in the used to in single The relaxation in the dimer of and single The proteins in a The that is in this is to that for and the of and G. PubMed Scopus Google Scholar), we that these segments are Å of in the of the This is with the C2 symmetry in the crystal, as a significant of for the relaxation the of the characterize the of the plexin-B1 that bind the three GTPases, in NMR of plexin-B1 in the with in of the active Rac1 and Rnd1, and proteins are in the NMR with a in the active the binding is to and a and that the same region of is involved in the interaction. This region of and as well as a long loop and a short and is involved in the binding of all three GTPases 3 and In are for and a region that is to the segment of the protein and also involved in the segments as binding by the the of the first and the long loop region show significant D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google the structure of the x-ray structure location of that significant as a of GTPase-plexin the structure of the Rho GTPase binding domain of with data are in The structure of the protein is in are in the structure and are by between that are in with the GTPases and that are by conformational of a NMR by I. 2005; PubMed Scopus Google has been NMR are the are in with the shows the for the plexin by Rac1 are for the region of the of the for a of the long loop that several in the such as not to a significant of binding D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). these are not directly involved in the they conformational of to the binding Rho GTPases through a and to the NMR and K. and M. and and D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google in a of binding for Rac1, the of the the segments and Rho GTPase and motif show that the segments are conserved in and family proteins are not in protein In they are not in any small This suggests that these segments and are unique and to plexin family the of for the we that plexins bind Rac1, Rnd1, and and have several in the first motif and are to bind the Rho GTPases with The tertiary structure of the protein shows that the motifs are brought together in a single binding we the same region is involved in the binding of all three GTPases, that the GTPases bind to plexin-B1 of a with the for are a of and data also show that are not formed that the GTPases for the same binding GTPase and involved in Rho GTPase binding are directly adjacent in to the region to involved and a in the is for the plexin-B1 GTPase The are and for active Rac1, Rnd1, and In a for of the as by and to by 4 D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The and the are adjacent to one that GTPase binding the of the to In the that the are to one in we to GTPases shows that are This is the NMR of the dimer are in that they have for of as well as for D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of active Rac1 a of dimer in a significant of these that the structure of the loop is by the GTPase and that the loop in the This is with data that the interaction with the GTPases the by a in a The binding of small GTPases to cytoplasmic of the plexin receptor in the of in cell signaling. In to between receptor proteins and small GTPases is the interaction between small Rho family GTPases and the is a and a of have been for this binding in the signaling mechanism. The of the domain structure and of GTPase binding to several of these the model we for receptor has important for cell signaling that involves Rho GTPases and guidance processes in the Rho GTPases through the used NMR spectroscopy with to the structure of the to the interaction with active Rac1, and Rnd1 and all three GTPases bind to the same This binding not the motif (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google of that to for Rho GTPase The motif is and well in several proteins D. A. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). binds to Rac1 and through a segment of motif The that a motif is for GTPase binding to plexin-B1 has a of a the of the motif to is known to all binding (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar, I. Y. Katoh H. M. 2004; PubMed Scopus Google Scholar, S. A. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). to the structure of the this is in the of and in the of the protein This is to the of to and and this important The is to the protein a change that the binding the GTPases. binding of GTPases to motifs not a the motif is In has been in proteins that part of the motif in a region of the that is part adjacent This is also the in the structure the motif the of and to the GTPase binding to motifs in proteins is by a of region M. W. J. Mol. Biol. 2004; PubMed Scopus Google Scholar). of the of such a conformational protein the motif bind to small Rho GTPases with in several segments of plexin the motif bind to by the NMR of is that of the plexin interacts with the a of This suggests that the homology of the motif in plexin-B1 is to GTPase binding by (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar). In of the of the are in plexin-B1 and one in 3 in H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar). the the that the structure of the protein is for GTPase binding and that the motif is not involved in binding to the three GTPases. The region that is involved in the interaction with the Rho GTPases is in and that the motifs involved in binding are brought together by the ubiquitin-like tertiary fold of the plexin domain. are well conserved plexins and also not in a motif for Rho protein GTPase and Cell of have that the plexin receptor has GTPase role by of certain Rho GTPases to the The these GTPases the of active that the actin Rac1 is involved in the of actin in cell for example H. Goodman C.S. Full Text Full Text PDF PubMed Scopus Google Scholar). of the active GTPase this with the function of plexin in growth H.G. Li W. Guan K.L. Genes Dev. 2002; PubMed Scopus Google Scholar). show that the plexin-B1 binds to the three Rho family GTPases with through a is that a role also to Rnd1 and RhoD. 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The binding of the we in the of not to GTPases In is a of receptors to the of GTPases in data are the of receptors GTPases, such GTPase as a principal signaling mechanism. in the Rho GTPase GTPase is by conformational in the in conformational are the that are binding of activated Rac1, Rnd1, in NMR of the protein are to of these the structure shows that the are one of the plexin domain to the are that the domain not significant conformational in that are the Rho GTPase binding This suggests that is not to involved in the involves the and I. Y. Katoh H. M. 2004; PubMed Scopus Google Scholar, I. Katoh H. M. J. 2004; PubMed Scopus Google that conformational are in the plexin-B1 cytoplasmic to the function of plexin-B1 In data between the cytoplasmic and of and also that active Rac1 and Rnd1, between and I. Y. Katoh H. M. 2004; PubMed Scopus Google Scholar, I. Katoh H. M. J. 2004; PubMed Scopus Google Scholar, S. A. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the is not part of the that are for the to the structure of the is in the receptor that of the domain and a the conformational that are in the Rho GTPase of a conformational change the fold of the data a for receptor This involves the of the cytoplasmic domain for the of Rho GTPases in GTPase by Destabilization of the of in Rac1 have that plexins are of small Rho GTPases (12Vikis H.G. Li W. He Z. Guan K.L. Proc. Natl. Sci. S. A. PubMed Scopus Google Scholar, H. A. I. Goodman C.S. A. Curr. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The NMR data in this show that the same of the plexin-B1 binds three Rho family GTPases, Rac1, Rnd1, and RhoD. role of the segment is with the function of Rac1 and Rnd1 in receptor I. Katoh H. M. J. 2004; PubMed Scopus Google Scholar, S. A. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). is not known binding also to receptor The of binding data is that the response of plexin to the binding of Rac1, and Rnd1 is with a in the signaling of the of the GTPase binding the structure of the Rho GTPase binding domain significant conformational are to between the and the cytoplasmic we data D. L. M. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), we that the Rho GTPase binding and are adjacent to one and is in the that binding of all three Rho GTPases in the of dimer to in to a model for the of Rho GTPases in cell signaling. The model in a as the of the and of and as K. N. Nat. Biol. 2003; PubMed Scopus Google Scholar, A. J.P. van K. J. Lu M. C. Puschel A.W. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the homology of the plexin extracellular domain to semaphorins, is that the extracellular of the receptor is also a of these extracellular active and receptors I. Katoh H. M. J. 2004; PubMed Scopus Google Scholar, T. Full Text Full Text PDF PubMed Scopus Google Scholar), also that the is binding to conformational that the dimerized of the receptor the extracellular as by and A. J.P. van K. J. Lu M. C. Puschel A.W. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The GTPase binding the region and the of this The model is the that the interaction of Rho GTPases with plexin not the structure of the receptor the cytoplasmic is not Rac1, Rnd1, binding is to the structure of the receptor protein as binding the to characterize the between the of the the change in the receptor the cytoplasmic to semaphorin as has been for plexin-B1 H.G. Li W. Guan K.L. Genes Dev. 2002; PubMed Scopus Google in of this of the in the of are the first of transmembrane receptors known to interact directly with small GTPases. The three Rho GTPases, Rac1, Rnd1, and to and to signaling in cells P. A. J. J. 2004; PubMed Scopus Google Scholar). we is these three GTPases, and not I. Puschel A.W. J. 2002; PubMed Google Scholar), bind to and and of the A- and B-family the of the interaction for a signaling and a model for In the signaling semaphorin binding the receptor this conformational also to the cytoplasmic The of the with the binding of active Rac1, Rnd1, and to a of GTPase and in the of extracellular GTPase binding the receptor for in the signaling mechanism. the of the extracellular is to the of that region of the In one of the GTPases, Rac1, is to involved in receptor localization H.G. Li W. Guan K.L. Genes Dev. 2002; PubMed Scopus Google Scholar). is in the cell J. S. 2002; Full Text Full Text PDF PubMed Scopus Google and is to of the cell the response of plexins to is to the growth this region a of Rho GTPases T. Full Text Full Text PDF PubMed Scopus Google Scholar, P. A. J. J. 2004; PubMed Scopus Google model implies that the receptor function to the of to the and of Rho GTPases. cell that has to has formed have a of active GTPases. This not for the plexin receptors in such a region to bind and to semaphorin guidance in with The bidirectional signaling that cells that are in is with the of certain active Rho family GTPases, not of growth are to these the they are several of this system by the multifunctional role of the GTPase as a in the cell signaling mechanism. of the of plexin-B1 have been by a joint x-ray and solution NMR The x-ray structure that the has a fold and is dimerized through a long NMR to the binding that plexin-B1 to interact with three Rho family GTPases, Rac1, Rnd1, as well as with RhoD. all three GTPases bind to the same of the fold. This GTPase binding includes conserved motifs that to to plexins. also that the is adjacent to the region and that of the GTPases the in The a model in GTPase in plexin This conformational change a for signaling that is to a multifunctional role in the of receptor of and Tamagnone of for and for the and the of the for the and of and of the for also and for data in this the has been by and the of of the by the of of of with

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