<i>Plasmodium falciparum</i> Hsp70-x: a heat shock protein at the host–parasite interface
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<i>Plasmodium falciparum</i> 70 kDa heat shock proteins (PfHsp70s) are expressed at all stages of the pathogenic erythrocytic phase of the malaria parasite life cycle. There are six PfHsp70s, all of which have orthologues in other plasmodial species, except for PfHsp70-x which is unique to <i>P. falciparum</i>. This research highlights a number of original results obtained by a detailed bioinformatics analysis of the protein. Large-scale sequence analysis indicated the presence of an extended transit peptide sequence of PfHsp70-x which potentially directs it to the endoplasmic reticulum (ER). Further analysis showed that PfHsp70-x does not have an ER-retention sequence, suggesting that the protein transits through the ER and is secreted into the parasitophorous vacuole or beyond into the erythrocyte cytosol. These results are consistent with experimental findings. Next, possible interactions between PfHsp70-x and exported <i>P. falciparum</i> Hsp40s or host erythrocyte Hsp40 were interrogated by modelling and docking. Docking results indicated that interaction between PfHsp70-x and each of the Hsp40s, regardless of biological feasibility, seems equally likely. This suggests that J domain might not provide the specificity in the formation of unique Hsp70-Hsp40 complexes, but that the specificity might be provided by other domains of Hsp40s. By studying different structural conformations of PfHsp70-x, it was shown that Hsp40s can only bind when PfHsp70-x is in a certain conformation. Additionally, this work highlighted the possible dependence of the substrate-binding domain residues on the orientation of the α-helical lid for formation of the substrate-binding pocket.
恶性疟原虫（Plasmodium falciparum）70 kDa热休克蛋白（PfHsp70s）在该疟疾寄生虫生命周期的致病性红细胞内阶段的所有时期均有表达。该家族共包含6种PfHsp70，除PfHsp70-x仅存在于恶性疟原虫（P. falciparum）中外，其余5种在其他疟原虫物种中均存在直系同源物。本研究通过对该蛋白的详细生物信息学分析，获得了多项原创性研究结果。大规模序列分析显示，PfHsp70-x存在一段延伸的转运肽序列，该序列可能将其引导至内质网（endoplasmic reticulum, ER）。进一步分析表明，PfHsp70-x不具备内质网驻留序列，这提示该蛋白会经内质网转运，并被分泌至纳虫空泡，或进一步进入红细胞胞质。上述研究结果与实验发现相符。随后，本研究通过建模与分子对接技术，探究了PfHsp70-x与恶性疟原虫（P. falciparum）分泌的Hsp40蛋白，或宿主红细胞Hsp40蛋白之间的潜在相互作用。分子对接结果显示，无论生物学可行性如何，PfHsp70-x与每一种Hsp40蛋白的结合概率似乎均相近。这一结果提示，J结构域（J domain）可能无法为特异性Hsp70-Hsp40复合物的形成提供结合特异性，而结合特异性或许由Hsp40蛋白的其他结构域所赋予。通过研究PfHsp70-x的不同结构构象，研究人员发现，仅当PfHsp70-x处于特定构象时，Hsp40蛋白才能与之结合。此外，本研究还揭示，底物结合结构域的氨基酸残基可能依赖于α螺旋盖子的取向，以形成底物结合口袋。
