Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles.
Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles.
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DOI：
10.1371/journal.ppat.1002958
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Baxter RH
中科院分区：
文献类型：
--
作者：
Le BV;Williams M;Logarajah S;Baxter RH
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. Anopheles mosquitoes transmit malaria, the world's most devastating parasitic disease, of which Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. Different populations of mosquitoes vary widely in how readily they become infected with malaria parasites, while some strains do not transmit malaria at all. The mosquitoes' innate immune system is a significant factor that may influence the level of malaria infection; in particular the thioester-containing protein 1 (TEP1) targets malaria parasites for destruction during their initial invasion of the body cavity. The TEP1 gene varies significantly across mosquito populations with two major classes of alleles, TEP1*S and TEP1*R. We report the three-dimensional molecular structure of the TEP1*S1 protein and compare it to the previously determined TEP1*R1 structure. Differences between the structures are localized around the active site and thioester bond, and correlate with a difference in stability of this bond within the two proteins and their interaction with a heterodimer of two other immune genes, LRIM1 and APL1C. These results shed light on the mechanism of mosquitoes' natural immunity to malaria infection.
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影响因子：
6.7
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
Frolet, Cecile;Thoma, Martine;Levashina, Elena A.
通讯作者：
Levashina, Elena A.
DOI：
10.1073/pnas.0704967104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Baxter, Richard H. G.;Chang, Chung-I;Deisenhofer, Johann
通讯作者：
Deisenhofer, Johann