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1: J Biol Chem. 2008 Oct 31;283(44):30412-20. Epub 2008 Aug 14.
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Intramolecular activation mechanism of the Dictyostelium LRRK2 homolog Roco protein GbpC.

van Egmond WN, Kortholt A, Plak K, Bosgraaf L, Bosgraaf S, Keizer-Gunnink I, van Haastert PJ.

Department of Cell Biochemistry, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands.

GbpC is a large multidomain protein involved in cGMP-mediated chemotaxis in the cellular slime mold Dictyostelium discoideum. GbpC belongs to the Roco family of proteins that often share a central core region, consisting of leucine-rich repeats, a Ras domain (Roc), a Cor domain, and a MAPKKKinase domain. In addition to this core, GbpC contains a RasGEF domain and two cGMP-binding domains. Here, we report on an intramolecular signaling cascade of GbpC. In vitro, the RasGEF domain of GbpC specifically accelerates the GDP/GTP exchange of the Roc domain. Moreover, cGMP binding to GbpC strongly stimulates the binding of GbpC to GTP-agarose, suggesting cGMP-stimulated GDP/GTP exchange at the Roc domain. The function of the protein in vivo was investigated by rescue analysis of the chemotactic defect of gbpC null cells. Mutants that lack a functional guanine exchange factor (GEF), Roc, or kinase domain are inactive in vivo. Together, the results suggest a four-step intramolecular activation mechanism of the Roco protein GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation of the GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain.

PMID: 18703517 [PubMed - in process]