Institut Pasteur, Unité d'Immunologie Structurale, 75015 Paris, France.
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5243-8. doi: 10.1073/pnas.1018692108. Epub 2011 Mar 14.
The human malaria parasite Plasmodium falciparum can cause infected red blood cells (iRBC) to form rosettes with uninfected RBC, a phenotype associated with severe malaria. Rosetting is mediated by a subset of the Plasmodium falciparum membrane protein 1 (PfEMP1) variant adhesins expressed on the infected host-cell surface. Heparin and other sulfated oligosaccharides, however, can disrupt rosettes, suggesting that therapeutic approaches to this form of severe malaria are feasible. We present a structural and functional study of the N-terminal domain of PfEMP1 from the VarO variant comprising the N-terminal segment (NTS) and the first DBL domain (DBL1α(1)), which is directly implicated in rosetting. We demonstrate that NTS-DBL1α(1)-VarO binds to RBC and that heparin inhibits this interaction in a dose-dependent manner, thus mimicking heparin-mediated rosette disruption. We have determined the crystal structure of NTS-DBL1α(1), showing that NTS, previously thought to be a structurally independent component of PfEMP1, forms an integral part of the DBL1α domain. Using mutagenesis and docking studies, we have located the heparin-binding site, which includes NTS. NTS, unique to the DBL α-class domain, is thus an intrinsic structural and functional component of the N-terminal VarO domain. The specific interaction observed with heparin opens the way for developing antirosetting therapeutic strategies.
人类疟原虫恶性疟原虫可导致受感染的红细胞（iRBC）与未受感染的 RBC 形成玫瑰花结，这是一种与严重疟疾相关的表型。玫瑰花结的形成是由感染宿主细胞表面表达的疟原虫膜蛋白 1（PfEMP1）变体黏附素的亚群介导的。然而，肝素和其他硫酸化寡糖可以破坏玫瑰花结，这表明针对这种严重疟疾形式的治疗方法是可行的。我们对恶性疟原虫 VarO 变体的 PfEMP1 N 端结构域进行了结构和功能研究，该结构域包括 N 端结构域（NTS）和第一个 DBL 结构域（DBL1α（1）），该结构域直接参与玫瑰花结的形成。我们证明 NTS-DBL1α（1）-VarO 可与 RBC 结合，肝素可呈剂量依赖性抑制这种相互作用，从而模拟肝素介导的玫瑰花结破坏。我们已经确定了 NTS-DBL1α（1）的晶体结构，表明 NTS，以前被认为是 PfEMP1 的结构独立成分，是 DBL1α 结构域的一个组成部分。通过突变和对接研究，我们定位了肝素结合位点，其中包括 NTS。NTS 是 DBL α 类结构域所特有的，因此是 N 端 VarO 结构域的固有结构和功能组成部分。与肝素观察到的特异性相互作用为开发抗玫瑰花结治疗策略开辟了道路。
