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J. Biol. Chem. 286 (29): 26093-26106

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Structural Basis of Rnd1 Binding to Plexin Rho GTPase Binding Domains (RBDs)*Formula

Hui Wang{ddagger}1, Prasanta K. Hota§12, Yufeng Tong{ddagger}, Buren Li{ddagger}, Limin Shen{ddagger}, Lyudmila Nedyalkova{ddagger}, Susmita Borthakur§, SoonJeung Kim§, Wolfram Tempel{ddagger}, Matthias Buck§||3, , and Hee-Won Park{ddagger}**4

From the {ddagger}Structural Genomics Consortium and
**Department of Pharmacology, University of Toronto, Toronto, Ontario M5G 1L5, Canada and
the Departments of §Physiology and Biophysics,
Neuroscience, and
||Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

ABSTRACT Back to Top

Abstract: Plexin receptors regulate cell adhesion, migration, and guidance. The Rho GTPase binding domain (RBD) of plexin-A1 and -B1 can bind GTPases, including Rnd1. By contrast, plexin-C1 and -D1 reportedly bind Rnd2 but associate with Rnd1 only weakly. The structural basis of this differential Rnd1 GTPase binding to plexin RBDs remains unclear. Here, we solved the structure of the plexin-A2 RBD in complex with Rnd1 and the structures of the plexin-C1 and plexin-D1 RBDs alone, also compared with the previously determined plexin-B1 RBD.Rnd1 complex structure. The plexin-A2 RBD·Rnd1 complex is a heterodimer, whereas plexin-B1 and -A2 RBDs homodimerize at high concentration in solution, consistent with a proposed model for plexin activation. Plexin-C1 and -D1 RBDs are monomeric, consistent with major residue changes in the homodimerization loop. In plexin-A2 and -B1, the RBD β3-β4 loop adjusts its conformation to allow Rnd1 binding, whereas minimal structural changes occur in Rnd1. The plexin-C1 and -D1 RBDs lack several key non-polar residues at the corresponding GTPase binding surface and do not significantly interact with Rnd1. Isothermal titration calorimetry measurements on plexin-C1 and -D1 mutants reveal that the introduction of non-polar residues in this loop generates affinity for Rnd1. Structure and sequence comparisons suggest a similar mode of Rnd1 binding to the RBDs, whereas mutagenesis suggests that the interface with the highly homologous Rnd2 GTPase is different in detail. Our results confirm, from a structural perspective, that Rnd1 does not play a role in the activation of plexin-C1 and -D1. Plexin functions appear to be regulated by subfamily-specific mechanisms, some of which involve different Rho family GTPases.

Key Words: Biophysics • Cell Migration • Crystallography • Neurodevelopment • Protein-Protein Interactions • Signal Transduction • Thermodynamics • Axon Guidance • Rho GTPase Rnd1

Received for publication October 22, 2010. Revision received May 20, 2011.


1 Both authors contributed equally to this work.

2 A postdoctoral fellow of the American Heart Association, Great Rivers Affiliate.

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3 To whom correspondence may be addressed: Case Western Reserve University, School of Medicine, Robbins Blvd., Rm. E607, 10900 Euclid Ave., Cleveland, OH 44106-4970. E-mail: matthias.buck{at}

4 To whom correspondence should be addressed: 101 College St., MaRS South Tower, Rm. 737, Toronto, Ontario M5G1L7, Canada. E-mail: heewon.park{at}

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