G-PROTEIN MECHANISMS - INSIGHTS FROM STRUCTURAL-ANALYSIS

This review is concerned with the structures and mechanisms of a super family of regulatory GTP hydrolases (G proteins). G proteins include R as and its close homologs, translation elongation factors, and heterot rimeric G proteins. These proteins share a common structural core, exe mplified by that of p21(ras) (Ras), and significant sequence identity, suggesting a common evolutionary origin. Three-dimensional structures of members of the G protein superfamily are considered in light of ot her biochemical findings about the function of these proteins. Relatio nships among G protein structures are discussed, and factors contribut ing to their low intrinsic rate of GTP hydrolysis are considered. Comp arison of GTP- and GDP-bound conformations of G proteins reveals how s pecific contacts between the gamma-phosphate of GTP and the switch II region stabilize potential effector-binding sites and how GTP hydrolys is results in collapse (or reordering) of these surfaces. A GTPase-act ivating protein probably binds to and stabilizes the conformation of i ts cognate G protein that recognizes the transition state for hydrolys is, and may insert a catalytic residue into the G protein active site. Inhibitors of nucleotide release, such as the beta gamma subunit of a heterotrimeric G protein, bind selectively to and stabilize the GDP-b ound state. Release factors, such as the translation elongation factor , Ts, also recognize the switch regions and destabilize the Mg2+-bindi ng site, thereby promoting GDP release. G protein-coupled receptors ar e expected to operate by a somewhat different mechanism, given that th e GDP-bound form of many G protein alpha subunits does not contain bou nd Mg2+.