Structure of the Harmonin PDZ2 and coiled-coil domains in a complex with CDHR2 tail and its implications
Structure of the Harmonin PDZ2 and coiled-coil domains in a complex with CDHR2 tail and its implications
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DOI：
10.1096/fj.202200403rr
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发表时间：
2022-07-01
期刊：
影响因子：
4.8
通讯作者：
Li，Jianchao
中科院分区：
文献类型：
--
作者：
Yan，Wenxia;Chen，Guanhao;Li，Jianchao
Harmonin是一种含有多个PDZ结构域的蛋白质，是毛细胞静纤毛和刷状缘微绒毛发育和维持所必需的。USH 1C基因突变可导致1C型Usher综合征，这是一种严重的遗传性疾病，其特征是听力和视力丧失。在这里，通过求解具有钙粘蛋白相关家族成员2尾部的复合物中Harmonin PDZ 2和卷曲螺旋结构域的高分辨率晶体结构，我们证明了位于Harmonin PDZ 2结构域中并在患者中发现的突变可能影响其稳定性，从而影响靶点结合能力。该结构还意味着卷曲螺旋结构域可以在高浓度下形成反平行二聚体，可能是当Harmonin在肠上皮的毛细胞静纤毛或肠上皮细胞的微绒毛中的上部尖端连接密度中经历液-液相分离时。晶体结构和生化分析为Harmonin突变导致Usher综合征、非综合征性耳聋或肠病提供了机制暗示。
Harmonin is a protein containing multiple PDZ domains and is required for the development and maintenance of hair cell stereocilia and brush border microvilli. Mutations in theUSH1Cgene can cause Usher syndrome type 1C, a severe inheritable disease characterized by the loss of hearing and vision. Here, by solving the high‐resolution crystal structure of Harmonin PDZ2 and coiled‐coil domains in a complex with the tail of cadherin‐related family member 2, we demonstrated that mutations located in the Harmonin PDZ2 domain and found in patients could affect its stability, and thus, the target binding capability. The structure also implies that the coiled‐coil domain could form antiparallel dimers under high concentrations, possibly when Harmonin underwent liquid–liquid phase separation in the upper tip‐link density in hair cell stereocilia or microvilli of enterocytes of the intestinal epithelium. The crystal structure, together with the biochemical analysis, provided mechanistic implications for Harmonin mutations causing Usher syndrome, non‐syndromic deafness, or enteropathy.