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Protein kinase R reveals an evolutionary model for defeating viral mimicry

Nels C Elde1, Stephanie J Child, Adam P Geballe

  • 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

Nature
|December 2, 2008
PubMed

Insights

Host proteins like protein kinase R (PKR) evolve to overcome pathogen mimicry. Evolutionary strategies, including positive selection in primates, allow PKR to evade viral mimics by adapting its recognition sites.

Area of Science:

  • Evolutionary biology
  • Immunology
  • Virology

Background:

  • Pathogens use molecular mimicry to evade host defenses.
  • Poxviruses encode K3L, a mimic of eukaryotic initiation factor 2 alpha (eIF2alpha), which is a substrate for protein kinase R (PKR).
  • PKR is a key component of the innate immune system in vertebrates.

Purpose of the Study:

  • To investigate the evolutionary strategies employed by host proteins to overcome pathogen mimicry.
  • To understand how PKR evolves to evade mimics like viral K3L.
  • To explore the molecular basis of the 'arms race' between host immunity and viral evasion tactics.

Main Methods:

  • Phylogenetic analysis of PKR evolution in primates.
  • Functional assays to assess PKR-eIF2alpha and PKR-K3L interactions.
  • Identification of positively selected sites and adaptive mutations in PKR.

Main Results:

  • PKR has undergone significant positive selection in primates.
  • Adaptive evolution at eIF2alpha recognition sites contributes to PKR's ability to evade K3L mimicry.
  • Multiple adaptive changes across PKR's surface enhance its efficacy against viral mimics.

Conclusions:

  • Host proteins can evolve to overcome pathogen mimicry through mechanisms like positive selection.
  • Evolutionary flexibility at protein interaction interfaces is crucial for host defense against viral evasion strategies.
  • The PKR-K3L system illustrates a dynamic molecular 'arms race' between host immunity and viral mimicry.

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