Molecular architecture of Gαo and the structural basis for RGS16-mediated deactivation
Kevin C. Slep,Michele A. Kercher,Thomas Wieland,Ching-Kang Chen,Melvin I. Simon,Paul B. Sigler +5 more
TLDR
The 2.9 Å crystal structure of the enigmatic, neuronal G protein Gαo in the GTP hydrolytic transition state, complexed with RGS16 is presented, affording insight to receptor, GAP and effector specificity.Abstract:
Heterotrimeric G proteins relay extracellular cues from heptahelical transmembrane receptors to downstream effector molecules. Composed of an α subunit with intrinsic GTPase activity and a βγ heterodimer, the trimeric complex dissociates upon receptor-mediated nucleotide exchange on the α subunit, enabling each component to engage downstream effector targets for either activation or inhibition as dictated in a particular pathway. To mitigate excessive effector engagement and concomitant signal transmission, the Gα subunit's intrinsic activation timer (the rate of GTP hydrolysis) is regulated spatially and temporally by a class of GTPase accelerating proteins (GAPs) known as the regulator of G protein signaling (RGS) family. The array of G protein-coupled receptors, Gα subunits, RGS proteins and downstream effectors in mammalian systems is vast. Understanding the molecular determinants of specificity is critical for a comprehensive mapping of the G protein system. Here, we present the 2.9 A crystal structure of the enigmatic, neuronal G protein Gαo in the GTP hydrolytic transition state, complexed with RGS16. Comparison with the 1.89 A structure of apo-RGS16, also presented here, reveals plasticity upon Gαo binding, the determinants for GAP activity, and the structurally unique features of Gαo that likely distinguish it physiologically from other members of the larger Gαi family, affording insight to receptor, GAP and effector specificity.read more
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Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets
TL;DR: This review considers the likelihood of several strategies for antagonizing the function of these oncogene alleles and their gene products, including the use of RGS proteins with Gαq selectivity, as well as their substrates, the heterotrimeric G-protein α subunits.
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Kinetic Scaffolding Mediated by a Phospholipase C–β and Gq Signaling Complex
G L Waldo,Tiffany K. Ricks,Stephanie N. Hicks,Matthew L. Cheever,Takeharu Kawano,Kazuhito Tsuboi,Xiaoyue Wang,Craig Montell,Tohru Kozasa,Tohru Kozasa,John Sondek,T. Kendall Harden +11 more
TL;DR: A dynamic catch-and-release mechanism used to sharpen spatiotemporal signals mediated by diverse sensory inputs is suggested and dramatically delay signal termination in vitro and in vivo.
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Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits.
Meera Soundararajan,Francis S. Willard,Adam J. Kimple,Andrew P. Turnbull,Linda J. Ball,Guillaume A. Schoch,Carina Gileadi,Oleg Fedorov,Elizabeth F. Dowler,Victoria A. Higman,Stephanie Q. Hutsell,Michael Sundström,Declan A. Doyle,David P. Siderovski +13 more
TL;DR: 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 Gα substrate, suggests that unique structural determinants specific to particular RGS protein/Gα pairings exist and could be used to achieve selective inhibition by small molecules.
Journal ArticleDOI
Structural features of the G-protein/GPCR interactions.
TL;DR: The structural details of the interfaces and recognition sites in complexes of sub-family A GPCRs with cognate G-proteins are reviewed, with special emphasis on the consequences of activation on GPCR structure.
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Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling
Nicolas Aznar,Krishna Midde,Ying Dunkel,Inmaculada Lopez-Sanchez,Yelena Pavlova,Arthur Marivin,Jorge Barbazan,Fiona Murray,Ulrich Nitsche,Klaus-Peter Janssen,Karl Willert,Ajay Goel,Miguel Abal,Mikel Garcia-Marcos,Pradipta Ghosh +14 more
TL;DR: Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.
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Structure of RGS4 Bound to AlF4−-Activated Giα1: Stabilization of the Transition State for GTP Hydrolysis
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GAIP and RGS4 Are GTPase-Activating Proteins for the Gi Subfamily of G Protein α Subunits
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