G Protein Heterodimers: New Structures Propel New Questions

The docking of G␣ to G␤␥ involves extensive contacts: *Department of Medicine binding of the G␣ N-terminal ␣ helix to the side of the Cardiovascular Division G␤ propeller parallel to its central tunnel and binding of Brigham and Women's Hospital the catalytic domain of G␣ to the top surface of the ␤ and Harvard Medical School propeller (see Figure 1). Removal of the N-terminal ␣ Boston, Massachusetts 02115 helix from G␣ prevents formation of G␣␤␥ heterotrimers † Department of Pharmacology (reviewed by Neer, 1995). The catalytic domain binds to and Biomolecular Engineering Research Center G␤ through a region called switch II, previously known Boston University to change conformation upon nucleotide binding and to Boston, Massachusetts 02215 be chemically cross-linkable to the G␤␥ subunit (Garcia-Higuera et al., 1996, and references therein). A number of salt bridges and the fit of G␤ Trp-99 into a hydrophobic The heterotrimeric G proteins transmit signals from a pocket on G␣ determine binding of G␣ to the top of the variety of cell surface receptors to enzymes and chan-propeller. Mutation of an equivalent Trp in yeast G␤ nels (reviewed by Neer, 1995). The heterotrimer consists disrupts G␤␥ binding to G␣, leading to constitutive acti-of an ␣ subunit that binds and hydrolyzes GTP and a vation of the yeast mating pathway (see Wall et al., 1995; pair of proteins, ␤ and ␥, that are tightly associated with Lambright et al., 1996). each other. The GTP-activated G␣ subunits dissociate GDP-liganded G␣ in a G␣␤␥ heterotrimer is different from G␤␥, and both subunits then activate their respec-from GDP-liganded G␣ alone (see references in Wall et tive effectors. The subunits stay separated until GTP is al., 1995; Lambright et al., 1996). This may be partly due hydrolyzed to GDP, whereupon they reassemble and to differences in crystal structures and crystal–crystal both become inactive. Therefore, the contact surface between G␣ and G␤␥ has major regulatory importance. Two groups have now independently determined the The new structures (Figure 1) reveal that the conformation of the GDP-liganded ␣ subunit in the heterotrimer is different from the GDP-liganded ␣ subunit alone (and also different from the crystallized GTP␥S-liganded form). They also reveal that the G␤ subunit folds into a highly symmetric ␤ propeller. Each propeller blade consists of a small four-stranded twisted ␤ sheet, the innermost ␤ strand being nearly parallel to the axis of the central tunnel (see schematic in Figure 2). This …