Liu Dongliang, Qian Dandan, Shen Huaizong, Gong Deshun
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
Sci Adv. 2021 Nov 5;7(45):eabj9748. doi: 10.1126/sciadv.abj9748. Epub 2021 Nov 3.
Mutations in the gene account for most cases of the Meckel-Gruber syndrome, the most severe ciliopathy with a 100% mortality rate. Here, we report a 3.3-Å cryo–electron microscopy structure of human Meckelin (also known as TMEM67 and MKS3). The structure reveals a unique protein fold consisting of an unusual cysteine-rich domain that folds as an arch bridge stabilized by 11 pairs of disulfide bonds, a previously uncharacterized domain named β sheet–rich domain, a previously unidentified seven-transmembrane fold wherein TM4 to TM6 are broken near the cytoplasmic surface of the membrane, and a coiled-coil domain placed below the transmembrane domain. Meckelin forms a stable homodimer with an extensive dimer interface. Our structure establishes a framework for dissecting the function and disease mechanisms of Meckelin.
该基因的突变是梅克尔-格鲁伯综合征（Meckel-Gruber syndrome）大多数病例的病因，梅克尔-格鲁伯综合征是最严重的纤毛病，死亡率达100%。在此，我们报道了人类梅克尔蛋白（Meckelin，也称为TMEM67和MKS3）分辨率为3.3 Å的冷冻电镜结构。该结构揭示了一种独特的蛋白质折叠，由一个不寻常的富含半胱氨酸的结构域组成，该结构域折叠成一座由11对二硫键稳定的拱桥，一个以前未被表征的名为富含β折叠的结构域，一个以前未被识别的七跨膜折叠（其中TM4至TM6在膜的细胞质表面附近断裂），以及一个位于跨膜结构域下方的卷曲螺旋结构域。梅克尔蛋白形成一个具有广泛二聚体界面的稳定同型二聚体。我们的结构为剖析梅克尔蛋白的功能和疾病机制建立了一个框架。
