On the Interaction Between Human IQGAP1 and Actin

22 IQGAPs are eukaryotic proteins which integrate signals from various sources and pass these 23 on the cytoskeleton. Understanding how they do this requires information on the interfaces 24 between the proteins. Here, it is shown that the calponin homology domain of human 25 IQGAP1 (CHD1) can be crosslinked with α-actin. The stoichiometry of the interaction was 26 1:1. A molecular model was built of the complex and associated bioinformatics analyses 27 predicted that the interaction is likely to involve an electrostatic interaction between Lys-240 28 of α-actin and Glu-30 of CHD1. These residues are predicted to be accessible and are not 29 involved in many intra-protein interactions; they are thus available for interaction with 30 binding partners. They are both located in regions of the proteins which are predicted to be 31 flexible and disordered; interactions between signalling molecules often involve flexible, 32 disordered regions. The predicted binding region in CHD1 is well conserved in many 33 eukaryotic IQGAP-like proteins. In some cases (e.g Dictyostelium discoideum and 34 Saccharomyces cerevisiae) protein sequence conservation is weak, but molecular modelling 35 reveals that a region of charged, polar residues in a flexible N-terminus is structurally well 36 conserved. Therefore we conclude that the calponin homology domains of IQGAP1-like 37 proteins interact initially through the electrostatic interaction identified here and that there 38 may be subsequent conformational changes to form the final complex.39