Abstract:
:Protein-protein interactions such as those between small G proteins and their effector proteins control most cell signaling pathways and thereby govern many cellular processes in both normal and disease states. Each small G protein interacts with several effectors, some shared between similar G proteins and others unique to a single GTPase. Although there is knowledge of the structural basis of these interactions, there is limited understanding of their thermodynamic basis. This is particularly significant because of the intrinsic conformational flexibility of the interacting partners. Here we have conducted a double mutant thermodynamic cycle for two key hydrophobic interactions in the Cdc42-ACK interface: Val42Cdc42-Ile463ACK and Leu174Cdc42-Leu449ACK. Val42 and Leu174 are known to be energetically important in this complex from previous thermodynamic studies, and their respective partners were predicted from the structure of the complex. Such a study has not been hitherto performed on any hydrophobic protein-protein interaction. The results confirm that a significant proportion of the overall interaction is dependent upon these residues, but in neither case is the direct interaction between the side chains the predominant energetic force. Indeed, the interaction of the side chains of Val42 and Ile463 appears to exert an energetic penalty. Rather, the stabilization of the complex, which requires the presence of these two pairs of residues, appears to be due to conformational changes, or interactions, that are not easily visualized in the structure of the complexes. In this respect, it is noteworthy that isolated Cdc42 shows regions of disorder and isolated ACK has no stable tertiary structure, whereas the Cdc42-ACK complex has a well-defined quaternary structure. Such changes may well be critical for the known selectivity of Cdc42 and related proteins such as Rho and Rac, for their wide range of effectors.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Elliot-Smith AE,Owen D,Mott HR,Lowe PNdoi
10.1021/bi701539xsubject
Has Abstractpub_date
2007-12-11 00:00:00pages
14087-99issue
49eissn
0006-2960issn
1520-4995journal_volume
46pub_type
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