Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy

Larry R. Masterson, Lei Shi, Emily Metcalfe, Jiali Gao, Susan S. Taylor, Gianluigi Veglia

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

Protein kinase A (PKA) is a ubiquitous phosphoryl transferase that mediates hundreds of cell signaling events. During turnover, its catalytic subunit (PKA-C) interconverts between three major conformational states (open, intermediate, and closed) that are dynamically and allosterically activated by nucleotide binding. We show that the structural transitions between these conformational states are minimal and allosteric dynamics encode the motions from one state to the next. NMR and molecular dynamics simulations define the energy landscape of PKA-C, with the substrate allowing the enzyme to adopt a broad distribution of conformations (dynamically committed state) and the inhibitors (high magnesium and pseudo-substrate) locking it into discrete minima (dynamically quenched state), thereby reducing the motions that allow turnover. These results unveil the role of internal dynamics in both kinase function and regulation.

Original languageEnglish (US)
Pages (from-to)6969-6974
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number17
DOIs
StatePublished - Apr 26 2011

Keywords

  • Allostery
  • Cooperativity
  • Intrinsically disordered proteins
  • Phospholamban
  • Substrate recognition

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