Work

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

Year: 2012

Type: article

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.

Source: PLoS Pathogens

DOI: 10.1371/journal.ppat.1002958

Authors: Binh V. Le, Marni Williams, Shankar Logarajah, Richard H. G. Baxter

Institutions: Yale University, University of Minnesota

Language: English

Topic: Malaria Research and Control

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $3,043