Open AccessMolecular Basis for Genetic Resistance of Anopheles gambiae to Plasmodium: Structural Analysis of TEP1 Susceptible and Resistant Alleles
Author(s) -
Binh M. Le,
Marni Williams,
Shankar Logarajah,
Richard Baxter
Publication year - 2012
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1002958
Subject(s) - anopheles gambiae , biology , thioester , genetics , allele , gene , microbiology and biotechnology , biochemistry , malaria , immunology , enzyme
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.