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Models of the cooperative mechanism for Rho effector recognition: implications for RhoA-mediated effector activation.

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons92249

Blumenstein,  Lars
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Blumenstein, L., & Ahmadian, M. R. (2004). Models of the cooperative mechanism for Rho effector recognition: implications for RhoA-mediated effector activation. The Journal of Biological Chemistry, 279(51), 53419-53426. doi:10.1074/jbc.M409551200.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0019-9C5F-C
Abstract
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