Molecular Basis for Genetic Resistance of to : Structural Analysis of TEP1 Susceptible and Resistant Alleles

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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.

Vyšlo v časopise: Molecular Basis for Genetic Resistance of to : Structural Analysis of TEP1 Susceptible and Resistant Alleles. PLoS Pathog 8(10): e32767. doi:10.1371/journal.ppat.1002958
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002958

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