Rajan Raghavan Sai Sundar, Turner Louise, Jensen Rasmus W, Johansen Nicolai Tidemand, Jensen Daniel Skjold, Gourdon Pontus, Zhang Jinqiu, Wang Yong, Theander Thor Grundtvig, Wang Kaituo, Lavstsen Thomas
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
Section for Transport Biology, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark.
Structure. 2023 Oct 5;31(10):1174-1183.e4. doi: 10.1016/j.str.2023.07.011. Epub 2023 Aug 14.
Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family.
严重的恶性疟原虫疟疾感染是由寄生虫通过多结构域的恶性疟原虫红细胞膜蛋白1（PfEMP1）粘附配体与人类内皮蛋白C受体（EPCR）结合，从而在微血管中滞留所引起的。利用低温电子显微镜（Cryo-EM）和PfEMP1序列多样性分析，我们发现A组PfEMP1 CIDRα1结构域通过EPCR结合位点的中央保守残基与相邻的DBLα1结构域相互作用，从而呈现紧凑构象。在与EPCR结合后，DBLα1结构域发生位移，CIDRα1的EPCR结合螺旋发生转动、扭结和扭曲，以达到重新排列的、稳定的EPCR结合构象。未结合状态以及向EPCR结合构象转变所需的过程可能代表了PfEMP1家族免疫逃逸的一种构象掩盖机制。
