Format

Send to

Choose Destination
Structure. 2014 Jan 7;22(1):59-69. doi: 10.1016/j.str.2013.10.012. Epub 2013 Dec 5.

PKA RIα homodimer structure reveals an intermolecular interface with implications for cooperative cAMP binding and Carney complex disease.

Author information

1
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
2
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
3
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA.
4
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
5
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: staylor@ucsd.edu.

Abstract

The regulatory (R) subunit is the cAMP receptor of protein kinase A. Following cAMP binding, the inactive PKA holoenzyme complex separates into two active catalytic (C) subunits and a cAMP-bound R dimer. Thus far, only monomeric R structures have been solved, which fell short in explaining differences of cAMP binding for the full-length protein as compared to the truncated R subunits. Here we solved a full-length R-dimer structure that reflects the biologically relevant conformation, and this structure agrees well with small angle X-ray scattering. An isoform-specific interface is revealed between the protomers. This interface acts as an intermolecular sensor for cAMP and explains the cooperative character of cAMP binding to the RIα dimer. Mutagenesis of residues on this interface not only leads to structural and biochemical changes, but is also linked to Carney complex disease.

PMID:
24316401
PMCID:
PMC3963464
DOI:
10.1016/j.str.2013.10.012
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center