Insights into G Protein Structure, Function, and Regulation

Abstract

In multicellular organisms from Caenorhabditis elegans to Homo sapiens, the maintenance of homeostasis is dependent on the continual flow and processing of information through a complex network of cells.Moreover, in order for the organism to respond to an ever-changing environment, intercellular signals must be transduced, amplified, and ultimately converted to the appropriate physiological response.The resolution of the molecular events underlying signal response and integration forms the basis of the signal transduction field of research.An evolutionarily highly conserved group of molecules known as heterotrimeric guanine nucleotide-binding proteins (G proteins) are key determinants of the specificity and temporal characteristics of many signaling processes and are the topic of this review.Numerous hormones, neurotransmitters, chemokines, local mediators, and sensory stimuli exert their effects on cells by binding to heptahelical membrane receptors coupled to heterotrimeric G proteins.These highly specialized transducers can modulate the activity of multiple signaling pathways leading to diverse biological responses.In vivo, specific combinations of G␣-and G␤␥subunits are likely required for connecting individual receptors to signaling pathways.The structural determinants of receptor-G protein-effector specificity are not completely understood and, in addition to involving interaction domains of these primary acting proteins, also require the participation of scaffolding and regulatory proteins.(Endocrine Reviews 24: 765-781, 2003) I. Introduction II.G Protein Structure III.Molecular Basis for G Protein Activation IV.Structural Determinants of Receptor-G Protein Specificity V. Receptor-Independent Activators of G Protein Signaling (AGS Proteins) VI.The Receptor-G␣ Protein Interface as a Therapeutic Target VII.G␣ Interaction with Effectors VIII.G␤␥ Interaction with Effectors A. G␤␥-Dimer composition directs effector and receptor coupling B. Structural determinants of effector specificity C. Novel G␤␥-effectors D. Additional role for G␤ 5 IX.Molecular Basis for G Protein Inactivation A. Intrinsic GTPase activity B. G␣ Interaction with GTPase-activating proteins (GAPs) X. Regulation of G Protein Function by Covalent Modification A. G protein lipidation B. The role of lipid modifications in G protein membrane association and consequent signaling functions XI.Advances for the Future: Investigating the Dynamic Nature of G Protein Signaling