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J. Biol. Chem., Vol. 279, Issue 51, 53419-53426, December 17, 2004

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Models of the Cooperative Mechanism for Rho Effector Recognition

IMPLICATIONS FOR RhoA-MEDIATED EFFECTOR ACTIVATION^*

Lars Blumenstein and Mohammad Reza Ahmadian

From the Max-Planck-Institute for Molecular Physiology, Department of Structural Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany

Activated GTPases of the Rho family regulate a spectrum of functionally diverse downstream effectors, initiating a network of signal transduction pathways by interaction and activation of effector proteins. Although effectors are defined as proteins that selectively bind the GTP-bound state of the small GTPases, there have been also several indications for a nucleotide-independent binding mode. By characterizing the molecular mechanism of RhoA interaction with its effectors, we have determined the equilibrium dissociation constants of several Rho-binding domains of three different effector proteins (Rhotekin, ROCKI/ROK /p160ROCK, PRK1/PKN where ROK is RhoA-binding kinase) for both RhoA · GDP and RhoA · GTP using fluorescence spectroscopy. In addition, we have identified two novel Rho-interacting domains in ROCKI, which bind RhoA with high affinity but not Cdc42 or Rac1. Our results, together with recent structural data, support the notion of multiple effector-binding sites in RhoA and strongly indicate a cooperative binding mechanism for PRK1 and ROCKI that may be the molecular basis of Rho-mediated effector activation.

Received for publication, August 19, 2004 , and in revised form, September 20, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 49-231-133-21-05; Fax: 49-231-133-21-99; E-mail: reza.ahmadian{at}mpi-dortmund.mpg.de.

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