The charge-dipole pocket: a defining feature of signaling pathway GTPase on/off switches.
Ras-like GTPases function as on/off switches in intracellular signaling pathways. Their on or off state is communicated through conformational changes in the so-called switch I and II regions. It is commonly believed that the distinguishing molecular features of these GTPases are well known. Here, however, I identify-through a Bayesian iterative analysis of GTPase evolutionary divergence-a previously undescribed switch II structural component that (along with previously described, functionally critical residues) most distinguish these signaling pathway on/off switches from other GTPases. In certain Ras-like GTPases this newly-identified component forms an aromatic pocket around the negative-dipole moment at the end of a switch II helix with a positively charged residue inserted into the pocket. This helix is oriented in a specific direction away from the GTPase core, but is reoriented dramatically upon disruption of the charge-dipole pocket. The charge-dipole pocket occurs in both the on and off states and both the charge-dipole pocket and an alternative configuration occur within the unit cell of a single crystal structure of Rab5a GTPase in the off state. Thus, the charge-dipole pocket configuration is closely associated, not with the on or off state, but rather with formation of the outward-oriented helix and, as a result, with restructuring of the switch II N-terminal region, which has a critical role both in sensing the on/off state and in mediating GTP hydrolysis and nucleotide exchange.
Institute for Genome Sciences and Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, 21201, USA. aneuwald@som.umaryland.edu
Andrew F
AF
Neuwald
D000595:Amino Acid Sequence; D001665:Binding Sites; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry* / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D055672:Static Electricity; D018631:ras Proteins / Q000737:chemistry* / Q000378:metabolism*
D044385:GTP-Binding Protein alpha Subunits; D006160:Guanosine Triphosphate; D018631:ras Proteins