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

Le, Binh V.; Williams, Marni; Logarajah, Shankar; Baxter, Richard G.

doi:10.1371/journal.ppat.1002958

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

Journal Article · Thu Oct 04 00:00:00 EDT 2012 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1002958· OSTI ID:1904164

Le, Binh V. ^[1]; Williams, Marni ^[2]; Logarajah, Shankar ^[2]; Baxter, Richard G. ^[2]

Yale Univ., New Haven, CT (United States); OSTI
Yale Univ., New Haven, CT (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Yale Univ., New Haven, CT (United States)

Sponsoring Organization:: National Center for Research Resources; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC), Biological and Environmental Research (BER)

OSTI ID:: 1904164

Journal Information:: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 10 Vol. 8; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Alleles
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Crystal structure
Hydrogen bonding
Hydrolysis
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Microbiology
Parasitology
Plasmodium
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Molecular Basis for Genetic Resistance of Anopheles gambiae to Plasmodium: Structural Analysis of TEP1 Susceptible and Resistant Alleles

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