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

PLoS Pathogens

Binh V. Le¹ 

[1] Department of Chemistry and Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut, United States of America

关键词: Hydrolysis;    Plasmodium;    Protein domains;    Crystal structure;    Chemical precipitation;    Alleles;    Hydrogen bonding;    Malaria;   

DOI  :  10.1371/journal.ppat.1002958

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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*S1cut) is significantly more susceptible to hydrolysis of its intramolecular thioester bond than TEP1*R1cut. TEP1*S1cut is stabilized in solution by the heterodimeric LRIM1/APL1C complex, which preserves the thioester bond within TEP1*S1cut. 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.

【 授权许可】

CC BY