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Entropic switch regulates myristate exposure in the HIV-1 matrix protein

Chun Tang1, Erin Loeliger, Paz Luncsford

  • 1Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250-5398, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 31, 2003
PubMed

Insights

The HIV-1 matrix protein

Area of Science:

  • Structural biology
  • Virology
  • Biochemistry

Background:

  • The myristoylated matrix protein (myr-MA) of HIV-1 regulates viral particle assembly and infectivity.
  • Myr-MA targets Gag polyproteins to lipid rafts and facilitates nuclear entry of the preintegration complex.
  • Membrane dissociation of myr-MA is crucial for HIV-1 infectivity.

Purpose of the Study:

  • To elucidate the molecular mechanism of myristyl group regulation in HIV-1 myr-MA.
  • To investigate the structural basis for myr-MA's membrane association and release.
  • To understand how Gag interactions influence myr-MA's myristyl switch.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy was used to study myr-MA.
  • Analysis of myr-MA in monomeric and trimeric states.
  • Investigation of myr-MA within a Gag-like construct.

Main Results:

  • Myr-MA exists in myristate-exposed [myr(e)] and -sequestered [myr(s)] states.
  • The tertiary structures of myr(e) and myr(s) states are highly similar, with minor adjustments for myristyl group sequestration.
  • Myristate exposure is coupled with trimerization; the myristyl group is sequestered in monomers and exposed in trimers.
  • Gag subdomains significantly enhance myristate exposure by promoting trimerization.

Conclusions:

  • HIV-1 myr-MA's myristyl switch is regulated by entropic modulation of a pre-existing equilibrium, not mechanical conformational changes.
  • Trimerization, driven by Gag interactions, is key to myristate exposure and membrane dissociation.
  • This mechanism differs from other known myristyl switches, highlighting a unique regulatory strategy in HIV-1.

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