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J Mol Biol. 2009 Jul 3;390(1):142-53. doi: 10.1016/j.jmb.2009.05.001. Epub 2009 May 7.

The charge-dipole pocket: a defining feature of signaling pathway GTPase on/off switches.

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  • 1Institute for Genome Sciences and Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, 21201, USA. aneuwald@som.umaryland.edu

Abstract

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.

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