The antigenic variation is an essential mechanism employed by the malaria parasite to establish a chronic infection in humans. Three major virulent proteins EMP1, RIFINs, and STEVOR have been implicated in contributing to the antigenic variation process and are encoded by multigene families in Plasmodium spp. The key virulence factor PfEMP1 is encoded by var genes, and it exhibits a mutually exclusive transcriptional switching between var genes, ensuring an individual parasite only transcribes a single var gene at a time. Expression of var genes is tightly regulated by two histone epigenetic methylation marks H3K36me3 and H3K9me3, of which the H3K36me3 mark is highly enriched on transcription start sites (TSSs) of suppressed var genes in P. falciparum. However, the mechanisms of H3K36me3 mark propagation on all the 59 var genes of P. falciparum are not known. Here, we have identified a PHD (Plant Homeodomain-like Domain) like domain present within the PfSET2 protein that specifically binds to the H3K36me2 mark, an intermediate product of the H3K36me3 mark formation on the nucleosome. Surprisingly, we have found that PHD - H3K36me2 interaction leads to stimulation of SET2 domain activity on the nucleosome substrates. The allosteric stimulation of the PfSET2 domain by PHD-like domain present within the same protein suggests a novel mechanism of H3K36me3 mark propagation on var genes of P. falciparum. This study proposes allosteric regulation of PfSET2 protein by H3K36me2 mark as an essential mechanism of var genes suppression to ensure successful antigenic variation by the malaria parasite.

抗原变异是疟原虫在人类中建立慢性感染所采用的基本机制。三种主要的毒力蛋白 EMP1、RIFIN 和 STEVOR 与抗原变异过程有关，由疟原虫中的多基因家族编码。关键毒力因子PfEMP1 由var基因编码，它在var基因之间表现出相互排斥的转录转换，确保单个寄生虫一次仅转录一个var基因。表达变种基因紧密由两个组蛋白调控的表观遗传甲基化标记 H3K36me3 和 H3K9me3，其中 H3K36me3 标记在恶性疟原虫中被抑制的var基因的转录起始位点 (TSS) 上高度富集。然而，H3K36me3 的机制标志着恶性疟原虫所有 59 个var基因的繁殖不知道。在这里，我们已经确定了 PfSET2 蛋白中存在的 PHD（植物同源域样域）样域，该域与 H3K36me2 标记特异性结合，H3K36me2 标记是核小体上 H3K36me3 标记形成的中间产物。令人惊讶的是，我们发现 PHD - H3K36me2 相互作用会刺激核小体底物上的 SET2 结构域活性。PfSET2 结构域受到同一蛋白质中存在的 PHD 样结构域的变构刺激表明 H3K36me3 标记在恶性疟原虫的var基因上传播的新机制。本研究提出通过 H3K36me2 标记对 PfSET2 蛋白的变构调节作为var基因抑制的重要机制，以确保疟疾寄生虫成功进行抗原变异。