Slep, Kevin C. and Kercher, Michele A. and Wieland, Thomas and Chen, Ching-Kang and Simon, Melvin I. and Sigler, Paul B. (2008) Molecular architecture of Gαo and the structural basis for RGS16-mediated deactivation. Proceedings of the National Academy of Sciences of the United States of America, 105 (17). pp. 6423-6428. ISSN 0027-8424. PMCID PMC2359805. doi:10.1073/pnas.0801569105. https://resolver.caltech.edu/CaltechAUTHORS:SLEpnas08
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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 Å crystal structure of the enigmatic, neuronal G protein Gαo in the GTP hydrolytic transition state, complexed with RGS16. Comparison with the 1.89 Å 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.
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Additional Information: | © 2008 by The National Academy of Sciences of the USA. Contributed by Melvin I. Simon, February 16, 2008 (received for review December 18, 2007). Published online before print April 23, 2008, doi: 10.1073/pnas.0801569105. We thank the staff at the Brookhaven National Laboratory (Upton, NY) National Synchrotron Light Source X25 beamline for support, Dr. L. Rice for advice on the Crystallography and NMR System software suite, and Dr. D. Siderovski and A. Kimple for advice on the manuscript. This work was supported in part by a grant from the National Institutes of Health (to P.B.S.) and a Life Sciences Research Foundation/Howard Hughes Medical Institute Fellowship (to M.A.K.). Data Deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3C7L and 3C7K). Author contributions: K.C.S., M.A.K., and P.B.S. designed research; K.C.S. and M.A.K. performed research; T.W., C.-K.C., and M.I.S. contributed new reagents/analytic tools; K.C.S., M.A.K., and P.B.S. analyzed data; and K.C.S. and M.I.S. wrote the paper. [P.B.S.] Deceased January 11, 2000. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0801569105/DCSupplemental. | |||||||||
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Subject Keywords: | G protein; GAP; RGS | |||||||||
Issue or Number: | 17 | |||||||||
PubMed Central ID: | PMC2359805 | |||||||||
DOI: | 10.1073/pnas.0801569105 | |||||||||
Record Number: | CaltechAUTHORS:SLEpnas08 | |||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:SLEpnas08 | |||||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | |||||||||
ID Code: | 11257 | |||||||||
Collection: | CaltechAUTHORS | |||||||||
Deposited By: | Archive Administrator | |||||||||
Deposited On: | 28 Jul 2008 22:22 | |||||||||
Last Modified: | 08 Nov 2021 21:56 |
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