IQGAPs are eukaryotic proteins which integrate signals from various sources and pass
these on the cytoskeleton. Understanding how they do this requires information on the interfaces between
the proteins. Here, it is shown that the calponin homology domain of human IQGAP1 (CHD1)
can be crosslinked with α-actin. The stoichiometry of the interaction was 1:1. A molecular model was
built of the complex and associated bioinformatics analyses predicted that the interaction is likely to involve an electrostatic
interaction between Lys-240 of -actin and Glu-30 of CHD1. These residues are predicted to be accessible and are
not involved in many intra-protein interactions; they are thus available for interaction with binding partners. They are both
located in regions of the proteins which are predicted to be flexible and disordered; interactions between signalling molecules
often involve flexible, disordered regions. The predicted binding region in CHD1 is well conserved in many eukaryotic
IQGAP-like proteins. In some cases (e.g Dictyostelium discoideum and Saccharomyces cerevisiae) protein sequence
conservation is weak, but molecular modelling reveals that a region of charged, polar residues in a flexible N-terminus is
structurally well conserved. Therefore we conclude that the calponin homology domains of IQGAP1-like proteins interact
initially through the electrostatic interaction identified here and that there may be subsequent conformational changes to
form the final complex.
Keywords: α-actin, calponin homology domain, CHD, IQGAP-like protein, protein flexibility, protein-protein crosslinking.
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