Skip NavigationSkip to Content
Return Return to Search Results

Two PKA RIa holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP

  1. Author:
    Lu, Tsan-Wen
    Wu, Jian
    Aoto, Phillip C
    Weng, Jui-Hung
    Ahuja, Lalima G
    Sun, Nicholas
    Cheng, Cecilia Y
    Zhang,Ping
    Taylor, Susan S

  2. Author Address

    Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093., Department of Pharmacology, University of California San Diego, La Jolla, CA 92093., Department of Biological Science, University of California San Diego, La Jolla, CA 92093., Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702., Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093; staylor@ucsd.edu.,
    1. Year: 2019
    2. Date: Aug 13
    3. Epub Date: 2019 07 30
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 116
    2. 33
    3. Pages: 16347-16356
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    Protein kinase A (PKA) holoenzyme, comprised of a cAMP-binding regulatory (R)-subunit dimer and 2 catalytic (C)-subunits, is the master switch for cAMP-mediated signaling. Of the 4 R-subunits (RIa, RIß, RIIa, RIIß), RIa is most essential for regulating PKA activity in cells. Our 2 RIa2C2 holoenzyme states, which show different conformations with and without ATP, reveal how ATP/Mg2+ functions as a negative orthosteric modulator. Biochemical studies demonstrate how the removal of ATP primes the holoenzyme for cAMP-mediated activation. The opposing competition between ATP/cAMP is unique to RIa. In RIIß, ATP serves as a substrate and facilitates cAMP-activation. The isoform-specific RI-holoenzyme dimer interface mediated by N3A-N3A 39; motifs defines multidomain cross-talk and an allosteric network that creates competing roles for ATP and cAMP. Comparisons to the RIIß holoenzyme demonstrate isoform-specific holoenzyme interfaces and highlights distinct allosteric mechanisms for activation in addition to the structural diversity of the isoforms.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1073/pnas.1906036116
  3. PMID: 31363049
  4. View record in Web of Science®
  5. WOS: 000481404300037
  6. PII : 1906036116

Library Notes

  1. Fiscal Year: FY2018-2019
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel