The Fifth People's Hospital of Shanghai and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, China.
Nat Commun. 2023 May 25;14(1):3012. doi: 10.1038/s41467-023-38303-0.
Pendrin (SLC26A4) is an anion exchanger expressed in the apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However its molecular structure has remained unknown, limiting our understanding of the structural basis of transport. Here, we determine the cryo-electron microscopy structures of mouse pendrin with symmetric and asymmetric homodimer conformations. The asymmetric homodimer consists of one inward-facing protomer and the other outward-facing protomer, representing coincident uptake and secretion- a unique state of pendrin as an electroneutral exchanger. The multiple conformations presented here provide an inverted alternate-access mechanism for anion exchange. The structural and functional data presented here disclose the properties of an anion exchange cleft and help understand the importance of disease-associated variants, which will shed light on the pendrin exchange mechanism.
Pendrin（SLC26A4）是一种在选定的上皮细胞顶膜中表达的阴离子交换器。Pendrin 的缺失会导致 Pendred 综合征，这是一种与感音神经性听力损失、甲状腺肿和血压降低相关的遗传疾病。然而，其分子结构仍然未知，限制了我们对运输结构基础的理解。在这里，我们确定了具有对称和非对称同源二聚体构象的小鼠 pendrin 的低温电子显微镜结构。非对称同源二聚体由一个内向构象的前体和另一个外向构象的前体组成，代表同时的摄取和分泌——这是 pendrin 作为电中性交换器的独特状态。这里呈现的多种构象为阴离子交换提供了一种倒易易位机制。所呈现的结构和功能数据揭示了阴离子交换裂隙的特性，并有助于理解与疾病相关变体的重要性，这将为 pendrin 交换机制提供启示。
