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Updated: Apr 5, 2026

Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

Published on: June 30, 2019

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An Isoform-Specific Myristylation Switch Targets Type II PKA Holoenzymes to Membranes

Ping Zhang1, Feng Ye2, Adam C Bastidas3

  • 1Department of Pharmacology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0654, USA.

Structure (London, England : 1993)
|August 18, 2015
PubMed

Insights

N-terminal myristylation acts as a membrane-anchoring switch for cyclic AMP-dependent protein kinase (PKA) RII holoenzymes, but not RI holoenzymes. This myristylation mechanism is independent of A Kinase Anchoring Proteins (AKAPs).

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Cyclic AMP-dependent protein kinase (PKA) is regulated by N-terminal myristylation of its catalytic (C) subunit.
  • PKA holoenzymes, composed of regulatory (R) and catalytic (C) subunits, are crucial for cellular signaling.
  • Limited structural data exists on myristylation's role in PKA membrane targeting.

Purpose of the Study:

  • To investigate the structural basis and functional implications of N-terminal myristylation in PKA holoenzyme membrane association.
  • To determine if myristylation serves as a membrane-targeting mechanism for different PKA holoenzyme subtypes (RI vs. RII).

Main Methods:

  • Crystal structure determination of RIα:myrC and RIIβ2:myrC2 holoenzymes.
  • Nanodisc synthesis for creating membrane mimetics.
  • Electron microscopy to visualize holoenzyme-membrane interactions.

Main Results:

  • The N-terminal myristylation site on the catalytic subunit functions as a flexible "switch".
  • This myristylation switch facilitates membrane anchoring specifically for RII holoenzymes, not RI holoenzymes.
  • Membrane targeting via myristylation is independent of A Kinase Anchoring Proteins (AKAPs).

Conclusions:

  • N-terminal myristylation provides a distinct mechanism for RII PKA holoenzyme membrane localization.
  • This myristylation-dependent membrane anchoring is a novel pathway, separate from AKAP-mediated recruitment.
  • Structural insights reveal the myristylation switch's role in regulating PKA localization and function.

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