9EDC

Reset Type-I Protein Kinase A Holoenzyme

9EDC の概要

• エントリーDOI: 10.2210/pdb9edc/pdb
• EMDBエントリー: 47944
• 分子名称: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase type I-alpha regulatory subunit, ADENOSINE-5'-TRIPHOSPHATE (3 entities in total)
• 機能のキーワード: kinase, regulator, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88659.89

構造登録者

Venkatakrishnan, V.,Buckley, T.,Laremore, T.N.,Armache, J.P.,Anand, G.S. (登録日: 2024-11-16, 公開日: 2025-04-23, 最終更新日: 2025-05-14)

主引用文献

Venkatakrishnan, V.,Laremore, T.N.,Buckley, T.S.C.,Armache, J.P.,Anand, G.S.
Multiplicity of Regulatory Subunit Conformations Defines Structural Ensemble of Reset Protein Kinase A Holoenzyme.
J.Am.Chem.Soc., 147:14174-14190, 2025

PubMed Abstract: How protein kinase A (PKA) is reset to a basal state following 3'5'-cyclic adenosine monophosphate (cAMP)-mediated activation is unknown. Here we describe the mechanism of cAMP-PKA type I signal termination leading to a reset of PKA by holoenzyme formation through the obligatory action of phosphodiesterases (PDEs). We report a catalytic subunit (Cα)-assisted mechanism for the reset of type I PKA and describe for the first time multiple structures of the reset PKA holoenzyme (RIα:Cα) that capture an ensemble of multiple conformational end-states through integrative electron microscopy and structural mass spectrometry approaches. Together these complementary methods highlight the large conformational dynamics of the regulatory subunit (RIα) within the tetrameric reset PKA holoenzyme. The cAMP-free reset PKA holoenzyme adopts multiple distinct conformations of RIα with contributions from the N-terminal linker and CNB-B dynamics. Our findings highlight the interplay between RIα, Cα, and PDEs (PDE8) in cAMP-PKA signalosomes to offer a new paradigm for PDE-mediated regulation of cAMP-PKA signaling.

PubMed: 40241376
DOI: 10.1021/jacs.4c16269

実験手法

ELECTRON MICROSCOPY (4.18 Å)