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J. Biol. Chem., Vol. 275, Issue 48, 37742-37751, December 1, 2000
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From the § Signal Transduction Laboratory, Institute of
Molecular and Cell Biology, 30 Medical Drive,
Singapore 117609, Republic of Singapore
We recently showed that BNIP-2 is a putative
substrate of the fibroblast growth factor receptor tyrosine
kinase and it possesses GTPase-activating activity toward the small
GTPase, Cdc42. The carboxyl terminus of BNIP-2 shares high homology to
the non-catalytic domain of Cdc42GAP, termed BCH (for
BNIP-2 and Cdc42GAP homology) domain. Despite the lack of obvious homology to any known catalytic domains of GTPase-activating proteins (GAPs), the BCH domain of BNIP-2
bound Cdc42 and stimulated the GTPase activity via a novel arginine-patch motif similar to that employed by one contributing partner in a Cdc42 homodimer. In contrast, the BCH domain of Cdc42GAP, although it can bind Cdc42, is catalytically inactive. This raises the
possibility that these domains might have other roles in the cell.
Using glutathione S-transferase recombinant proteins,
immunoprecipitation studies, and yeast two-hybrid assays, it was found
that BNIP-2 and Cdc42GAP could form homo and hetero complexes via their
conserved BCH domains. Molecular modeling of the BNIP-2 BCH homodimer
complex and subsequent deletion mutagenesis helped to identify the
region 217RRKMP221 as the major BCH interaction
site within BNIP-2. In comparison, deletion of either the
arginine-patch 235RRLRK239 (necessary for GAP
activity) or region 288EYV290 (a Cdc42 binding
sequence) had no effect on BCH-BCH interaction. Extensive data base
searches showed that the BCH domain is highly conserved across species.
The results suggest that BCH domains of BNIP-2 and Cdc42GAP represent a
novel protein-protein interaction domain that could potentially
determine and/or modify the physiological roles of these molecules.
The BNIP-2 and Cdc42GAP Homology Domain of BNIP-2 Mediates
Its Homophilic Association and Heterophilic Interaction with
Cdc42GAP*
§,¶, and
*
This work was supported by the Institute of Molecular and
Cell Biology, Singapore.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to the results of this work.
¶
Structural Bioinformatics Scientist.
To whom correspondence should be addressed. Tel.: 65-874-3737;
Fax: 65-779-1117; E-mail: mcbgg@imcb.nus.edu.sg.
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