Proteins and Regulators of GProteins

Small G proteins and their activators

Ras and RasGAP. As a prototype of small G proteins, the structure of p21Ras (Pai et al., 1990) reveals a variation of the mononucleotide binding fold (Fig. 17.1.43A; Table 17.1.19; also see The Classical Mononucleotide-Binding Fold). Like many small G proteins, the intrinsic GTPase activity of Ras is quite low and requires GTPase activation protein (GAP) to increase the enzymatic rate of GTP hydrolysis. The structure of p120GAP is all a-helical (Fig. 17.1.43B; Scheffzek et al., 1996). The structure of a complex between Ras and the Ras guanine-nucleotide-exchange-factor region of the son of sevenless (Sos) reveals a tight association between them that buries 3600 A2 of surface area. This results in the dissociation of the nucleotide from Ras due to alteration of the conformation of the switch 1 and 2 regions (Boriack-Sjodin et al., 1998). The Ras-ex-change-factor region of Sos consists of N- and C-terminal a-helical domains, with the C-ter-minal a-helical domain interacting with Ras (Fig. 17.1.43C). Another group of Ras-like GTP-binding proteins is the Ran family that are involved in nuclear transport. The structure of

Ran-GppNHp has also been determined (Vetter et al., 1999).

Rho and RhoGAP. The Rho family of small G proteins includes Rho, Rac, and Cdc42Hs. They regulate the phosphorylation rate of a variety of proteins involved in cell proliferation and cytoskeleton formation. The intrinsic GTPase activity of the Rho family of G proteins (i.e., the rate of hydrolysis of GTP to GDP) is slow but can be increased by 105-fold upon interacting with Rho family of G protein activators. Several crystal structures of Rho family G proteins and their complexes with RhoGAPs have been determined, thus revealing the molecular mechanism of the activation of Rho by its activator proteins (Fig. 17.1.43D). Among them, the structures of Rac1 (Hirshberg et al., 1997) and p50rhoGAP (Barrett et al., 1997), as well as the complexes between RhoA and RhoGAP (Rittinger et al., 1997b), Cdc42Hs and p50rhoGAP, and Rac1 and Tiam 1 have been published (Rittinger et al., 1997a; Worthy-lake et al., 2000; Table 17.1.19). The structure of Rho assumes a typical Ras-like G protein fold and RhoGAP adopts an a-helical fold similar to the p120GAP. In the structure of the complexes, an Arg residue on RhoGAP interacts with the P-loop of Rho, presumably to stabilize the transition state of the GTP hydrolysis.

Large GTP-binding proteins

Unlike the Ras-like small G-proteins, the family of large GTP-binding proteins is characterized by higher molecular weight and higher intrinsic GTPase activity. Members of this family include guanylate-binding proteins 1 and 2 (GBP1 and 2), Mx, and dynamin. The crystal structure of an intact human GBP1 with a molecular weight of 67,000 reveals a two-domain fold (Fig. 17.1.43E; Prakash et al., 2000). The N-terminal domain resembles a modified Ras-like G-protein fold with several insertions compared to the canonical Ras structure. The C-terminal domain is elongated and consists of seven a-helices including one that is 118-A long. GBP1 lacks the conserved nucleotide binding motif (Asn/Thr)-Lys-X-Glu as observed in all Ras-like G-proteins. GBP1 is stable without the bound nucleotide, whereas Ras is not.

Heterotrimeric G proteins and their regulators

G protein trimer. G protein-coupled transmembrane receptor signaling cascades are ubiquitous throughout eukaryotic cells and util

Structural Biology

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