ABSTRACT
Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Galpha subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Galpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Galpha, RGS domain binding consequently accelerates Galpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Galpha substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential Galpha selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/Galpha complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the Galpha substrate, suggests that unique structural determinants specific to particular RGS protein/Galpha pairings exist and could be used to achieve selective inhibition by small molecules.
Subject(s)
GTP-Binding Protein alpha Subunits/metabolism , RGS Proteins/chemistry , RGS Proteins/metabolism , Apoproteins/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/chemistry , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Humans , Models, Molecular , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Subunits/chemistry , Protein Subunits/metabolismABSTRACT
We have assigned 1H, 13C and 15N resonances of the Bright/ARID DNA-binding domain from the human JARID1C protein, a newly discovered histone demethylase belonging to the JmjC domain-containing protein family.
Subject(s)
Magnetic Resonance Spectroscopy/methods , Oxidoreductases, N-Demethylating/chemistry , Amino Acid Sequence , Carbon Isotopes/chemistry , Histone Demethylases , Humans , Molecular Sequence Data , Molecular Weight , Nitrogen Isotopes/chemistry , Protein Structure, Tertiary , ProtonsABSTRACT
We have assigned 1H, 13C and 15N resonances of the RGS domain from the human RGS14 protein, a multi-domain member of the RGS (Regulators of G-protein signalling) family of proteins, important in the down-regulation of specific G-protein signalling pathways.
