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Molecular and Cellular Biology, January 1999, p. 602-611, Vol. 19, No. 1
Cold Spring Harbor Laboratory, Cold Spring
Harbor, New York 11724,1 and
Department
of Biochemistry and Cell Biology, State University of New York
at Stony Brook, Stony Brook, New York 117942
Received 4 June 1998/Returned for modification 6 July 1998/Accepted 15 September 1998
Pak1 protein kinase of Schizosaccharomyces pombe, a
member of the p21-GTPase-activated protein kinase (PAK) family,
participates in signaling pathways including sexual differentiation and
morphogenesis. The regulatory domain of PAK proteins is thought to
inhibit the kinase catalytic domain, as truncation of this region
renders kinases more active. Here we report the detection in the
two-hybrid system of the interaction between Pak1 regulatory domain and
the kinase catalytic domain. Pak1 catalytic domain binds to the same highly conserved region on the regulatory domain that binds Cdc42, a
GTPase protein capable of activating Pak1. Two-hybrid, mutant, and
genetic analyses indicated that this intramolecular interaction rendered the kinase in a closed and inactive configuration. We show
that Cdc42 can induce an open configuration of Pak1. We propose that
Cdc42 interaction disrupts the intramolecular interactions of Pak1,
thereby releasing the kinase from autoinhibition.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Genetic Evidence for Pak1 Autoinhibition and Its Release
by Cdc42
and
*
Corresponding author. Mailing address: Cold Spring
Harbor Laboratory, Cold Spring Harbor, NY 11724. Phone: (516) 367-8376. Fax: (516) 367-8381. E-mail: wigler{at}cshl.org.
Present address: Tularik, Inc., South San Francisco, CA 94080.
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