The deadly symptoms of malaria occur as Plasmodium parasites replicate within blood cells. Members of several variant surface protein families are expressed on infected blood cell surfaces. Of these, the largest and most ubiquitous are the Plasmodium-interspersed repeat (PIR) proteins, with more than 1,000 variants in some genomes. Their functions are mysterious, but differential pir gene expression associates with acute or chronic infection in a mouse malaria model. The membership of the PIR superfamily, and whether the family includes Plasmodium falciparum variant surface proteins, such as RIFINs and STEVORs, is controversial. Here we reveal the structure of the extracellular domain of a PIR from Plasmodium chabaudi. We use structure-guided sequence analysis and molecular modeling to show that this fold is found across PIR proteins from mouse- and human-infective malaria parasites. Moreover, we show that RIFINs and STEVORs are not PIRs. This study provides a structure-guided definition of the PIRs and a molecular framework to understand their evolution.

疟疾的致命症状发生在疟原虫在血细胞内复制时。几种变异表面蛋白家族的成员在受感染的血细胞表面表达。其中最大和最普遍的是疟原虫穿插重复（PIR）蛋白，在某些基因组中有1000多个变体。它们的功能是神秘的，但在小鼠疟疾模型中，差异性pir基因表达与急性或慢性感染有关。PIR超家族的成员，以及该家族是否包括恶性疟原虫变体表面蛋白，例如RIFIN和STEVOR，都存在争议。在这里，我们揭示了疟原虫chabaudi的PIR的胞外域的结构。我们使用结构指导的序列分析和分子建模来显示这种折叠是在小鼠和人类感染性疟原虫的PIR蛋白中发现的。此外，我们证明RIFIN和STEVOR不是PIR。这项研究提供了PIR的结构指导定义和理解其演变的分子框架。