Guruprasad Lalitha, Tanneeru Karunakar, Guruprasad Kunchur
School of Chemistry, University of Hyderabad, Hyderabad 500046, India.
Protein Pept Lett. 2011 Jun;18(6):634-41. doi: 10.2174/092986611795222786.
The virulent form of malaria is caused by Plasmodium falciparum that infects red blood cells. In order to survive inside the host, the parasite remodels the infected erythrocytes by exporting more than 300 effector proteins outside the parasitophorous vacuole membrane into the cytosol. The main feature of all the export proteins is the presence of a pentapeptide sequence motif; RxLxE/Q/D. This sequence motif is hydrolysed between L-x and the proteins with the acetylated new N-terminus xE/Q/D are exported. The enzyme responsible for this hydrolysis is plasmepsin V which is one of the ten aspartic proteases in P. falciparum. In order to understand the structural rationale for the specificity of this protease towards cleavage of the above motif, we generated three-dimensional models of seven plasmepsins (I, V to X) for which experimental structures are not available and compared these along with the crystal structures of three P. falciparum plasmepsins (II to IV). The structure comparisons revealed the importance of Tyr13, Glu77 and Ala117 specific to plasmepsin V that facilitates the accommodation of arginine at P₃ in the RxLxE/Q/D motif. Our analysis correlates the structure-function relationship of plasmepsin V.
恶性疟疾是由感染红细胞的恶性疟原虫引起的。为了在宿主体内存活，该寄生虫通过将300多种效应蛋白输出到寄生泡膜之外进入细胞质，对受感染的红细胞进行重塑。所有输出蛋白的主要特征是存在一个五肽序列基序：RxLxE/Q/D。该序列基序在L-x之间被水解，带有乙酰化新N端xE/Q/D的蛋白质被输出。负责这种水解的酶是疟原虫天冬氨酸蛋白酶V，它是恶性疟原虫中的十种天冬氨酸蛋白酶之一。为了理解这种蛋白酶对上述基序切割特异性的结构原理，我们生成了七种疟原虫天冬氨酸蛋白酶（I、V至X）的三维模型，这些模型没有实验结构，并将它们与三种恶性疟原虫天冬氨酸蛋白酶（II至IV）的晶体结构进行了比较。结构比较揭示了疟原虫天冬氨酸蛋白酶V特有的Tyr13、Glu77和Ala117的重要性，它们有助于在RxLxE/Q/D基序的P₃处容纳精氨酸。我们的分析关联了疟原虫天冬氨酸蛋白酶V的结构-功能关系。
