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

Title: 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 ^[1]; Logarajah, Shankar ^[1]; Baxter, Richard G. ^[1]

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.

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

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

Grant/Contract Number:: K22AI085112-01; P41RR012408; P41GM103473

OSTI ID:: 1904164

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

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Anopheles gambiae TEP1 forms a complex with the coiled-coil domain of LRIM1/APL1C following a conformational change in the thioester domain Williams, Marni; Contet, Alicia; Hou, Chun-Feng David PLOS ONE, Vol. 14, Issue 6 https://doi.org/10.1371/journal.pone.0218203	journal	June 2019
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59 BASIC BIOLOGICAL SCIENCES
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Title: Molecular Basis for Genetic Resistance of Anopheles gambiae to Plasmodium: Structural Analysis of TEP1 Susceptible and Resistant Alleles

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