Plasmodium falciparum Erythrocyte Membrane Protein 1 Diversity in Seven Genomes - Divide and Conquer
Plasmodium falciparum Erythrocyte Membrane Protein 1 Diversity in Seven Genomes - Divide and Conquer
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DOI：
10.1371/journal.pcbi.1000933
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发表时间：
2010-09-01
影响因子：
4.3
通讯作者：
Lavstsen, Thomas
中科院分区：
文献类型：
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作者：
Rask, Thomas S.;Hansen, Daniel A.;Lavstsen, Thomas
var基因编码的高变恶性疟原虫红细胞膜蛋白1（PfEMP 1）家族介导感染的红细胞与人内皮细胞的细胞粘附。阻断细胞粘附的抗体是疟疾流行人群获得免疫力的重要介质。基于PfEMP 1的疫苗模仿自然获得性免疫的发展取决于对进化的PfEMP 1多样性的透彻理解，平衡抗原变异与保守的受体结合亲和力。这项研究重新定义和重新分类PfEMP 1的结构域从七个基因组。在399个不同的PfEMP 1序列的结构域的分析允许识别几个新的结构域类，和高度的PfEMP 1结构域组成的顺序，包括保守的结构域盒并不总是与建立组A-E划分PfEMP 1。一种新的迭代同源块（HB）检测方法，允许识别628个保守的最小PfEMP 1构建块，平均描述83%的PfEMP 1序列。使用HB，域类之间的相似性进行了测定，并发现在许多情况下，达菲结合样（DBL）域子类的主要域类的杂交种。与此相关，在DBL亚结构域S2和S3之间发现了重组热点。介绍了VarDom服务器，可以从中检索有关域类和同源块的信息，并可以对新序列进行分类。发现了几个保守的序列元件，包括：（1）在所有DBL结构域中保守的残基，预测其相互作用并将三个DBL亚结构域保持在一起，（2）DBL α结构域中潜在的整联蛋白结合位点，（3）在A组var基因中保守的酰化基序，表明N-末端N-肉豆蔻酰化，（4）PfEMP 1结构域间区域被认为是弹性无序结构，和（5）几个保守的预测磷酸化位点。理想情况下，PfEMP 1的这种全面分类将为var/PfEMP 1表达和功能的未来研究提供平台。
The var gene encoded hyper-variable Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates cytoadhesion of infected erythrocytes to human endothelium. Antibodies blocking cytoadhesion are important mediators of malaria immunity acquired by endemic populations. The development of a PfEMP1 based vaccine mimicking natural acquired immunity depends on a thorough understanding of the evolved PfEMP1 diversity, balancing antigenic variation against conserved receptor binding affinities. This study redefines and reclassifies the domains of PfEMP1 from seven genomes. Analysis of domains in 399 different PfEMP1 sequences allowed identification of several novel domain classes, and a high degree of PfEMP1 domain compositional order, including conserved domain cassettes not always associated with the established group A-E division of PfEMP1. A novel iterative homology block (HB) detection method was applied, allowing identification of 628 conserved minimal PfEMP1 building blocks, describing on average 83% of a PfEMP1 sequence. Using the HBs, similarities between domain classes were determined, and Duffy binding-like (DBL) domain subclasses were found in many cases to be hybrids of major domain classes. Related to this, a recombination hotspot was uncovered between DBL subdomains S2 and S3. The VarDom server is introduced, from which information on domain classes and homology blocks can be retrieved, and new sequences can be classified. Several conserved sequence elements were found, including: (1) residues conserved in all DBL domains predicted to interact and hold together the three DBL subdomains, (2) potential integrin binding sites in DBL alpha domains, (3) an acylation motif conserved in group A var genes suggesting N-terminal N-myristoylation, (4) PfEMP1 inter-domain regions proposed to be elastic disordered structures, and (5) several conserved predicted phosphorylation sites. Ideally, this comprehensive categorization of PfEMP1 will provide a platform for future studies on var/PfEMP1 expression and function.