C subunits binding to the protein kinase A RI alpha dimer induce a large conformational change.

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Publication Type Journal Article
School or College College of Pharmacy
Department Pharmacology & Toxicology
Creator Blumenthal, Donald K.
Other Author Heller, William T.; Virgil, Dominico; Brown, Simon
Title C subunits binding to the protein kinase A RI alpha dimer induce a large conformational change.
Date 2004-04-30
Description We present structural data on the RI alpha isoform of the cAMP-dependent protein kinase A that reveal, for the first time, a large scale conformational change within the RI alpha homodimer upon catalytic subunit binding. This result infers that the inhibition of catalytic subunit activity is not the result of a simple docking process but rather is a multi-step process involving local conformational changes both in the cAMP-binding domains as well as in the linker region of the regulatory subunit that impact the global structure of the regulatory homodimer. The results were obtained using small-angle neutron scattering with contrast variation and deuterium labeling. From these experiments we derived information on the shapes and dispositions of the catalytic subunits and regulatory homodimer within a holoenzyme reconstituted with a deuterated regulatory subunit. The scattering data also show that, despite extensive sequence homology between the isoforms, the overall structure of the type I alpha holoenzyme is significantly more compact than the type II alpha isoform. We present a model of the type I alpha holoenzyme, built using available high-resolution structures of the component subunits and domains, which best fits the neutron-scattering data. In this model, the type I alpha holoenzyme forms a flattened V shape with the RI alpha dimerization domain at the point of the V and the cAMP-binding domains of the RI alpha subunits with their bound catalytic subunits at the ends.
Type Text
Publisher American Society for Biochemistry and Molecular Biology (ASBMB)
Volume 279
Issue 18
First Page 19084
Last Page 19090
Subject Protein Kinase; cAMP
Subject MESH Binding Sites; Cyclic AMP-Dependent Protein Kinases; Dimerization; Protein Binding; Recombinant Proteins; X-Ray Diffraction
Language eng
Bibliographic Citation Heller WT, Vigil D, Brown S, Blumenthal DK, Taylor SS, Trewhella J. C subunits binding to the protein kinase A RI alpha dimer induce a large conformational change. J Biol Chem. 2004 Apr 30;279(18):19084-90. Epub 2004 Feb 25. Retrieved September 14, 2006 from http://www.jbc.org/cgi/content/full/279/18/19084
Rights Management Copyright © American Society for Biochemistry and Molecular Biology, J Biol Chem., 279, 19084-19090, 2004.
Format Medium application/pdf
Identifier ir-main,392
ARK ark:/87278/s6z32h06
Setname ir_uspace
ID 704554
Reference URL https://collections.lib.utah.edu/ark:/87278/s6z32h06
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