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Abstract
Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). The intrinsic GTP hydrolysis activity of small GTPases is generally low and is accelerated by GAPs. GEFs promote GDP dissociation from small GTPases to allow for GTP binding, which results in a conformational change of two highly flexible segments, called switch I and switch II, that enables binding of the gamma phosphate and allows small GTPases to interact with downstream effectors. For several decades, crystal structures of many GEFs and GAPs have been reported and have shown tremendous structural diversity. In this review, we focus on the latest structural studies of GEFs. Detailed pictures of the variety of GEF mechanisms at atomic resolution can provide insights into new approaches for drug discovery.
Highlights
Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan
We summarize the guanine-nucleotide exchange factors (GEFs) mechanism based on structural work
In addition to structural rearrangements of the switch regions, another common mechanism has been observed for nucleotide release, in which is the insertion of projection residues towards the Mg2+ binding site (Sec2:Sec4, Vps9:Ara7) or electrostatic repulsion effects between an acidic residue of a GEF and the phosphate group (Vps9, TRAPP)
Summary
We highlighted the well-established structural mechanisms of GEFs. MSS4:Rab and SmgGDS:RhoAfarnesylated , exhibit dramatic structural changes of the bound small GTPases, leading to local protein unfolding (Figure 6). Both the MSS4 and SmgGDS proteins are known as chaperons in addition to their GEF function. The nucleotide recognition regions (P loop, switch I, and switch II) are almost ordered in in thethe unbound form, butbut these regions are largely disordered in both upon binding of the regulator. Unbound form, these regions are largely disordered in proteins both proteins upon binding of the Disordered regions are shown as dashed lines. The color scheme and other descriptions follow those of regulator.
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