Small GTPase

From Academic Kids

In biology, small GTPases are small (20-25 KDa) proteins that bind to guanosine triphosphate GTP. This family of proteins are homologous to Ras GTPases and also called the Ras superfamily GTPases. Small GTPases regulate a wide variety of processes in the cell, including growth, cellular differentiation, cell movement and lipid vesicle transport. Heterotrimeric G-proteins and small GTPases share common futures as GTPases but they have slightly different structures and mechanisms of action.

Contents

GTPase•GTP (ON) and GTPase•GDP (OFF)

Small GTPases act as molecular switches in signaling pathways, which act to regulate functions of other proteins. They are active or 'ON' when it is bound to GTP and inactive or 'OFF' when bound to GDP. Activation and deactivation of small GTPases can be regarded as occurring in a cycle, between the GTP-bound and GDP-bound form, regulated by other regulatory proteins. The inactive form of GTPases (GDP-form) are activated by a class of proteins called Guanosine Nucleotide Exchange Factors (GEFs). GEFs catalyse nucleotide exchange by encouraging the release of GDP from the small GTPase (by displacement of the small GTPase-associated Mg2+ ion) and GDP's replacement by GTP (which is in at least a 10-fold excess within the cell) . Inactivation of the active small GTPase is achieved through hydrolysis of the GTP by the small GTPase's intrinsic GTP hydrolytic activity. The rate of GTP hydrolysis for small GTPases is generally too slow to create physiologically relevant transient signals, and thus requires another class of regulatory proteins to accelerate this activity, the GTPase Activating Proteins (GAPs).

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Small_GTPase_cycle.jpg
Image:Small_GTPase_cycle.jpg

Another class of regulatory proteins, the Guanosine Nucleotide Dissociation Inhibitors (GDIs), bind to the GDP-bound form of Rho and Rab small GTPases and not only prevent exchange (maintaining the small GTPase in an off-state), but also prevent the small GTPase from localizing at the membrane, which is their place of action.

The Ras superfamily

There are more than a hundred proteins in the Ras superfamily. Based on structure, sequence and function, the Ras superfamily is divided into eight main families, each of which is further divided into subfamilies: Ras, Rho, Rab, Arf, Ran, Rheb, Rad and Rit. Each subfamily shares the common core G domain, which provides essential GTPase and nucleotide exchange activity. The surrounding sequence helps determine the functional specificity of the small GTPase, for example the 'Insert Loop', common to the Rho subfamily, specifically contributes to binding to effector proteins such as IQGAP and WASP.

References

Technical

  • Marc Symons and Yoshimi Takai, (2000) "Ras GTPases: Singing in Tune"
  • Hall, A. & Nobes, C. D. Rho GTPases "Molecular switches that control the organization and dynamics of the actin cytoskeleton." Philos Trans R Soc Lond B Biol Sci 355, 965-970 (2000).
  • Shields, J. M., Pruitt, K., McFall, A., Shaub, A. & Der, C. J. "Understanding Ras: 'it ain't over 'til it's over'." Trends Cell Biol 10, 147-154 (2000).
  • Vetter, I. R. & Wittinghofer, A. "The guanine nucleotide-binding switch in three dimensions." Science 294, 1299-1304 (2001).
  • Cox, A. D. & Der, C. J. "Ras family signaling: therapeutic targeting." Cancer Biol Ther 1, 599-606 (2002).
  • Sahai, E. & Marshall, C. "Rho-GTPases and Cancer." Nature Reviews Cancer 2, 133-142 (2002).
Science's STKE http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/68/pe1de:Kleine GTPase

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