Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Nat Commun. 2022 Jul 13;13(1):4047. doi: 10.1038/s41467-022-31720-7.
Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes. The parasite Toxoplasma gondii blocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectedly remain silenced. Here we define a core region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. Cellular, biochemical, mutational, and structural data demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. TgIST binding to this newly exposed site at the STAT1 dimer interface alters its conformation and prevents the recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription.
信号转导子和转录激活子（STAT）蛋白从细胞表面受体传递信号，驱动免疫反应基因的转录。寄生虫刚地弓形虫通过分泌内在无序蛋白 TgIST 来阻断 STAT1 介导的基因表达，该蛋白易位到宿主细胞核内，与磷酸化的 STAT1 二聚体结合，并占据新生转录位点，这些位点出人意料地保持沉默。在这里，我们定义了 TgIST 内部重复序列中的一个核心区域，该区域对于阻断 STAT1 介导的基因表达是必需和充分的。细胞、生化、突变和结构数据表明，TgIST 的重复区域在与 STAT1 二聚体结合时会采用螺旋构象。结合界面由 STAT1 SH2 结构域中的两个环形成的凹槽定义，该凹槽在二聚化过程中重新定向。TgIST 与 STAT1 二聚体界面上这个新暴露的位点的结合改变了其构象，并阻止了共转录激活因子的募集，从而定义了转录受阻的机制。
