6NO7

Crystal Structure of the full-length wild-type PKA RIa Holoenzyme

Summary for 6NO7

• Entry DOI: 10.2210/pdb6no7/pdb
• Related: 2QCS
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase type I-alpha regulatory subunit, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: pka, ria holoenzyme, atp-dependent, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 335931.47

Authors

Lu, T.,Wu, J.,Taylor, S.S. (deposition date: 2019-01-15, release date: 2019-07-24, Last modification date: 2024-10-23)

Primary citation

Lu, T.W.,Wu, J.,Aoto, P.C.,Weng, J.H.,Ahuja, L.G.,Sun, N.,Cheng, C.Y.,Zhang, P.,Taylor, S.S.
Two PKA RI alpha holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP.
Proc.Natl.Acad.Sci.USA, 116:16347-16356, 2019

PubMed 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 (RIα, RIβ, RIIα, RIIβ), RIα is most essential for regulating PKA activity in cells. Our 2 RIαC holoenzyme states, which show different conformations with and without ATP, reveal how ATP/Mg 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 RIα. In RIIβ, ATP serves as a substrate and facilitates cAMP-activation. The isoform-specific RI-holoenzyme dimer interface mediated by N3A-N3A' motifs defines multidomain cross-talk and an allosteric network that creates competing roles for ATP and cAMP. Comparisons to the RIIβ holoenzyme demonstrate isoform-specific holoenzyme interfaces and highlights distinct allosteric mechanisms for activation in addition to the structural diversity of the isoforms.

PubMed: 31363049
DOI: 10.1073/pnas.1906036116

Experimental method

X-RAY DIFFRACTION (3.55 Å)