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Vol. 14, Issue 4, 1624-1637, April 2003
Department of Biochemistry and Biophysics, University of
California, San Francisco, California 94143-0407
Intersectin 1L is a scaffolding protein involved in endocytosis
that also has guanine nucleotide exchange activity for Cdc42. In the
context of the full-length protein, the catalytic exchange activity of
the DH domain is repressed. Here we use biochemical methods to dissect
the mechanism for this inhibition. We demonstrate that the intersectin
1L SH3 domains, which bind endocytic proteins, directly inhibit the
activity of the DH domain in assays for both binding and exchange of
Cdc42. This inhibitory mechanism seems to act through steric hindrance
of Cdc42 binding by an intramolecular interaction between the
intersectin 1L SH3 domain region and the adjacent DH domain.
Surprisingly, the mode of SH3 domain binding is other than through the
proline peptide binding pocket. The dual role of the SH3 domains in
endocytosis and repression of exchange activity suggests that the
intersectin 1L exchange activity is regulated by endocytosis. We show
that the endocytic protein, dynamin, competes for binding to the SH3
domains with the neural Wiskott-Aldrich Syndrome protein, an actin
filament nucleation protein that is a substrate for activated Cdc42.
Swapping of SH3 domain binding partners might act as a switch
controlling the actin nucleation activity of intersectin 1L.
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