Gtpases

Regulatory GTPases form a large, evolutionarily related superfamily of enzymes that catalyze the hydrolysis of GTP to GDP and inorganic orthophosphate. The importance of these GTP-binding proteins lies, however, in the diverse regulatory activities that they acquire upon GTP binding and that are terminated by GTP hydrolysis. The GTPases thus act as molecular switches, active in the GTP-bound form and inactive in the GDP-bound form. GTP binding and GTP hydrolysis are both tightly regulated by other proteins. These proteins thus control a GTPase catalytic cycle and determine the fraction of time that the GTPase will spend in the active states. Alternatively, the regulatory proteins can independently turn the switch on or off in response to appropriate signals.

All the GTPases share a conserved structure around the GTP-binding site, with three identifiable regions of conserved amino-acid sequence. More closely related families share further sequence similarities. The individual families of GTPases are defined by the activities that they regulate and by their conserved structures. Each family is discussed under separate entries.  

1. Multiple initiation factors and elongation factors required for translation on ribosomes are regulatory GTPases. Their GTP-triggered functions include the recruitment of aminoacyl-tRNAs to the ribosome, participation in peptide bond formation and the associated movement of the nascent protein on the ribosome. This structurally and functionally diverse group also includes proteins involved in translocation of nascent proteins across membranes, such as the signal recognition particle. Elongation factor Tu (EF-Tu) from Escherichia coli is the historic prototype of the GTPase superfamily. Several proteins involved with co-translational, signal sequence-mediated translocation of nascent proteins through membranes are GTP-binding proteins more distantly related to this group.

2. Small, monomeric GTP-binding proteins (SMGs) constitute a large family of structurally related GTPases, most in the 20- to 25-kDa size range. They mediate numerous functions in eukaryotic cells, including activation of protein kinase signaling cascades, regulation of cytoskeleton structure, nuclear import/export, budding and docking of membrane vesicles involved in subcellular organellar trafficking, and so on.

3. Heterotrimeric GTP-binding regulatory proteins, often referred to as G proteins, organize and convey signals from cell surface receptors to cellular effector proteins, such as adenylyl cyclase, cyclic GMP phosphodiesterase, ion channels, phospholipase C, protein kinases, and so on. Individual G proteins (about 20 in total) display distinct but nonunique selectivity among receptors and effectors. Both the GTP-binding a subunits (~40 kDa), which include a domain similar to the SMGs, and the tightly associated b and g subunits convey signals to distinct effectors.

4. Dynamins are GTP-binding cytoskeletal proteins involved in the budding of endocytic vesicles. They are homologous to the other GTP-binding proteins only in the immediate region of the GTP-binding pocket. Dynamins also interact with the bg subunits of the heterotrimeric G proteins.

5. Tubulins, the structural proteins of eukaryotic microtubules, are also GTPases but are only distantly related to the regulatory GTPases. Polymerization of microtubules is regulated in part by GTP binding to tubulin.

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