Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles.
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.
Department of Chemistry and Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut, United States of America.
Binh V
BV
Le
Marni
M
Williams
Shankar
S
Logarajah
Richard H G
RH
Baxter
D000818:Animals; D000852:Anopheles / Q000235:genetics / Q000276:immunology* / Q000469:parasitology*; D018360:Crystallography, X-Ray; D006868:Hydrolysis; D007113:Immunity, Innate; D019476:Insect Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008288:Malaria / Q000276:immunology / Q000469:parasitology; D010962:Plasmodium berghei / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*; D020033:Protein Isoforms / Q000737:chemistry; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
D019476:Insect Proteins; C540280:LRIM1 protein, Anopheles gambiae; D020033:Protein Isoforms; C544265:TEP1 protein, Anopheles gambiae