Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles

PLoS Pathog. 2012;8(10):e1002958. doi: 10.1371/journal.ppat.1002958. Epub 2012 Oct 4.

Abstract

Thioester-containing protein 1 (TEP1) is a central component in the innate immune response of Anopheles gambiae to Plasmodium infection. Two classes of TEP1 alleles, TEP1*S and TEP1*R, are found in both laboratory strains and wild isolates, related by a greater or lesser susceptibility, respectively to both P. berghei and P. falciparum infection. We report the crystal structure of the full-length TEP1*S1 allele which, while similar to the previously determined structure of full-length TEP1*R1, displays flexibility in the N-terminal fragment comprising domains MG1-MG6. Amino acid differences between TEP1*R1 and TEP1*S1 are localized to the TED-MG8 domain interface that protects the thioester bond from hydrolysis and structural changes are apparent at this interface. As a consequence cleaved TEP1*S1 (TEP1*S1(cut)) is significantly more susceptible to hydrolysis of its intramolecular thioester bond than TEP1*R1(cut). TEP1*S1(cut) is stabilized in solution by the heterodimeric LRIM1/APL1C complex, which preserves the thioester bond within TEP1*S1(cut). These results suggest a mechanism by which selective pressure on the TEP1 gene results in functional variation that may influence the vector competence of A. gambiae towards Plasmodium infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anopheles / genetics
  • Anopheles / immunology*
  • Anopheles / parasitology*
  • Crystallography, X-Ray
  • Hydrolysis
  • Immunity, Innate
  • Insect Proteins / chemistry*
  • Insect Proteins / genetics*
  • Insect Proteins / metabolism
  • Malaria / immunology
  • Malaria / parasitology
  • Plasmodium berghei / immunology*
  • Plasmodium falciparum / immunology*
  • Protein Isoforms / chemistry
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary

Substances

  • Insect Proteins
  • LRIM1 protein, Anopheles gambiae
  • Protein Isoforms
  • TEP1 protein, Anopheles gambiae

Associated data

  • PDB/4D93
  • PDB/4D94