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Like key witnesses in a detective story, protein crystal structures can surprise, intrigue, mislead, or instruct us--and often do all four at once. On page 954 of this issue, Mixon et al. (1) serve up an intriguing surprise: Crystals of the guanosine diphosphate (GDP) form of alpha sub i1 , a G protein alpha subunit that mediates hormonal inhibition of adenylyl cyclase, reveal G alpha monomers linked, head-to-tail, in endless polymers. I suspect that the inference that similar G alpha polymers exist and function in vivo is a red herring. Instead, at least to this armchair sleuth, this polymer and other clues hint at a solution to a fascinating molecular puzzle at the heart of G protein signaling: How do receptors, in combination with G Beta gamma, trigger GDP release and G protein activation?
The 16 trimeric (alpha Beta gamma) G proteins of vertebrates relay messages from hormone and sensory) receptors to effector targets that mediate or regulate heart rate, contraction of smooth muscle, synaptic transmission, endocrine secretion, olfaction, vision, and many other functions. In each case the receptor turns on the G protein by promoting exchange of guanosine 5'-triphosphate (GTP) for GDP bound to the G alpha subunit, followed by dissociation of alpha GTP and the G Beta gamma dimer from the receptor and from each other. The appropriate effector protein is then regulated by alpha GTP or G Beta gamma (or both) until bound GTP is converted to GDP, allowing alpha GDP to reassociate with G Beta gamma and turn off the signal (2, 3).
Previous G alpha crystal structures provided three-dimensional (3D) views of GTP-induced conformational change (4, 5) and the guanosine triphosphatase (GTPase) catalytic mechanism (6, 7) but no evidence for any kind of polymer. The alpha sub i1 GDP polymer is made possible by a small folded domain, composed of sequence from both the amino (orange) and carboxyl (yellow) termini of each monomer (the N-C domain) (see figure). (Figure omitted) Previous G alpha structures showed only the Ras-like (white) and a-helical (gray) domains. In the alpha sub i1 GDP polymer, the new domain tucks neatly into a...