Regulation of Small GTPases by GEFs, GAPs, and GDIs

Abstract

Small GTPases use GDP/GTP alternation to actuate a variety of functional switches that are pivotal for cell dynamics. The GTPase switch is turned on by GEFs, which stimulate dissociation of the tightly bound GDP, and turned off by GAPs, which accelerate the intrinsically sluggish hydrolysis of GTP. For Ras, Rho, and Rab GTPases, this switch incorporates a membrane/cytosol alternation regulated by GDIs and GDI-like proteins. The structures and core mechanisms of representative members of small GTPase regulators from most families have now been elucidated, illuminating their general traits combined with scores of unique features. Recent studies reveal that small GTPase regulators have themselves unexpectedly sophisticated regulatory mechanisms, by which they process cellular signals and build up specific cell responses. These mechanisms include multilayered autoinhibition with stepwise release, feedback loops mediated by the activated GTPase, feed-forward signaling flow between regulators and effectors, and a phosphorylation code for RhoGDIs. The flipside of these highly integrated functions is that they make small GTPase regulators susceptible to biochemical abnormalities that are directly correlated with diseases, notably a striking number of missense mutations in congenital diseases, and susceptible to bacterial mimics of GEFs, GAPs, and GDIs that take command of small GTPases in infections. This review presents an overview of the current knowledge of these many facets of small GTPase regulation.

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

“…RAS protein activity is tightly regulated by Guanine Nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs). Constitutive activation of the RAS protein, in which RAS is unable to hydrolyze GTP, leads to cancer and other diseases [1,9,12] . Activating RAS mutations have been observed in 30% of human tumors [2,13] ; KRAS is the most commonly mutated isoform, mutated in 25%-30% of human cancers [3,13] .…”

“…Approximately 80% of KRAS mutations are found in codon 12, whereas approximately 60% of NRAS mutations are found in codon 61, with 35% in codon 12 [2,14] . HRAS mutations are equally divided between codons 12 and 61 [2,14] .…”

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

“…It is accepted that guanine nucleotide exchange factors (GEFs), which activate small GTPases by stimulating exchange of GDP for GTP, also have important roles in specifying the subcellular localization and downstream effectors of GTP-bound GTPases (reviewed in ref. 3). Arf GTPases are activated by GEFs characterized by a conserved Sec7 domain which is responsible for stimulating GDP/GTP exchange.…”

Assessing the Influence of Mutation on GTPase Transition States by Using X‐ray Crystallography, 19F NMR, and DFT Approaches

“…The turnover number of GTP hydrolysis by RhoA is accelerated 3.9×10 4 fold on binding the GTPase‐activating protein RhoGAP 3. The molecular basis of this acceleration has been investigated in structural studies on wild‐type (WT) RhoA/RhoGAP TSA complexes4 that conjugate GDP with square planar AlF 4 − or trigonal MgF 3 − surrogates for PO 3 − in the “true” TS.…”