Article
- The EMBO Journal (2004) 23, 1051 - 1062
- doi:10.1038/sj.emboj.7600124
Published online: 26 February 2004
Subject Category:
The nucleotide exchange factor Cdc24p may be regulated by auto-inhibition
Yukiko Shimada1,a, Philippe Wiget1,2, Marie-Pierre Gulli1, Efrei Bi3 and Matthias Peter2
- Swiss Institute for Experimental Cancer Research (ISREC), Epalinges/VD, Switzerland
- Swiss Federal Institute of Technology Zurich (ETH), Institute of Biochemistry, Zurich, Switzerland
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
Correspondence to:
Matthias Peter, Swiss Federal Institute of Technology Zurich (ETH), Institute of Biochemistry, ETH Hoenggerberg HPM G 6.2, 8093 Zurich, Switzerland. Tel.: +41 1 632 3134; Fax: +41 1 632 1269; E-mail: matthias.peter@bc.biol.ethz.ch
aPresent address: Department of Biochemistry, University of Geneva, 8093 Geneva, Switzerland
Received 2 July 2003; Accepted 19 January 2004
Abstract
Site-specific activation of the Rho-type GTPase Cdc42p by its guanine-nucleotide exchange factor (GEF) Cdc24p is critical for the establishment of cell polarity. Here we show that binding of Cdc24p to the small GTPase Rsr1p/Bud1p is required for its recruitment to the incipient bud site. Rsr1p/Bud1p binds to the CH-domain of Cdc24p, which is essential for its function in vivo. We have identified a cdc24-mutant allele, which is specifically defective for bud-site selection. Our results suggest that Cdc24p is auto-inhibited by an intramolecular interaction with its carboxy-terminal PB1-domain. Rsr1p/Bud1p appears to activate the GEF activity of Cdc24p in vivo, possibly by triggering a conformational change that dissociates the PB1-domain from its intramolecular binding site. Genetic experiments suggest that Bem1p functions as a positive regulator of Cdc24p by binding to the PB1-domain of Cdc24p, thereby preventing its re-binding to the intramolecular inhibitory site. Taken together, our results support a two-step molecular mechanism for the site-specific activation of Cdc24p, which involves Rsr1p/Bud1p and the adaptor protein Bem1p.
Keywords:
- auto-inhibition,
- Cdc24p,
- Cdc42p,
- cell polarity,
- GEF regulation,
- Rsr1p/Bud1p
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