Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

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.

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

“…The GEFs that control Rho GTPases activation are divided into two families: Dbl and DOCK [ 4 , 69 , 73 ]. In the Dbl family, we can find αPIX, Vav1, Tiam-1, Tiam-2/STEF, RasGRF, Sos1, Dbl, RhoGAP, p115RhoGEF, and Trio.…”

“…Moreover, it plays an important role in neurogenesis, as it participates in the progenitor cell formation and also in their differentiation into neurons [ 102 ]. Cdc42 regulation of these functions requires its activation by different GEFs such as Dbs, intersectin (ITSN), Prex1, Tiam1, Vav1–3, and Fgd5 [ 4 ]. ITSN-1 was linked to neurodegenerative diseases, as its mRNA expression is increased in AD brain samples [ 103 ].…”

“…GDIs prevent dissociation of GDP bound to the GTPase, consequently, keeping the small GTPase sequestered and inactive in the cytosol. Thus, the process by which the small GTPases pass from the active to the inactive configuration and vice versa, together with the actions of GEFs, GAPs, and GDIs on GTPases, is called the GTPases cycle [ 4 ] ( Figure 1 ).…”

Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

“…A distinguishing feature of these proteins is that they alternate between an inactive GDP-bound and an active GTP-bound state (Cherfils and Zeghouf, 2013;Lin et al, 2018;Toma-Fukai and Shimizu, 2019). This molecular switch is mediated by GAPs, responsible for GTP hydrolysis to GDP, and GEFs, which catalyze the exchange of GDP to GTP (Bos et al, 2007) (Figure 1).…”

“…Rat sarcoma (Ras) superfamily of small guanosine-5′-triphosphate (GTP)ases regulate many essential cellular activities such as cell signaling, membrane trafficking and cytoskeleton dynamics ( Vetter and Wittinghofer, 2001 ; Zhen and Stenmark, 2015 ; Casalou et al, 2016 , 2019 ; Toma-Fukai and Shimizu, 2019 ). Although Ras small GTPases control crucial physiological functions in cell homeostasis, several superfamily members are involved in the aberrant activation of signaling cascades that play a central role in a broad spectrum of human diseases, including cancer ( Aspenström, 2018 ; Casalou et al, 2020 ; Gopal Krishnan et al, 2020 ).…”