Department of Second Dental Center, Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, China.
Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Nat Commun. 2023 Feb 11;14(1):767. doi: 10.1038/s41467-023-36367-6.
EDA is a tumor necrosis factor (TNF) family member, which functions together with its cognate receptor EDAR during ectodermal organ development. Mutations of EDA have long been known to cause X-linked hypohidrotic dysplasia in humans characterized by primary defects in teeth, hair and sweat glands. However, the structural information of EDA interaction with EDAR is lacking and the pathogenic mechanism of EDA variants is poorly understood. Here, we report the crystal structure of EDA C-terminal TNF homology domain bound to the N-terminal cysteine-rich domains of EDAR. Together with biochemical, cellular and mouse genetic studies, we show that different EDA mutations lead to varying degrees of ectodermal developmental defects in mice, which is consistent with the clinical observations on human patients. Our work extends the understanding of the EDA signaling mechanism, and provides important insights into the molecular pathogenesis of disease-causing EDA variants.
EDA 是肿瘤坏死因子（TNF）家族的一员，它与同源受体 EDAR 在外胚层器官发育过程中共同发挥作用。EDA 的突变早已被认为是导致人类 X 连锁少汗性外胚层发育不良的原因，其特征是牙齿、头发和汗腺的主要缺陷。然而，EDA 与 EDAR 相互作用的结构信息尚不清楚，EDA 变异体的致病机制也知之甚少。在这里，我们报告了 EDA C 端 TNF 同源结构域与 EDAR N 端富含半胱氨酸结构域结合的晶体结构。通过生化、细胞和小鼠遗传学研究，我们表明不同的 EDA 突变导致小鼠的外胚层发育缺陷程度不同，这与人类患者的临床观察一致。我们的工作扩展了对 EDA 信号机制的理解，并为疾病相关 EDA 变异体的分子发病机制提供了重要的见解。
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