Tetraspanins play critical roles in various physiological processes, ranging from cell adhesion to virus infection. The members of the tetraspanin family have four membrane-spanning domains and short and large extracellular loops, and associate with a broad range of other functional proteins to exert cellular functions. Here we report the crystal structure of CD9 and the cryo-electron microscopic structure of CD9 in complex with its single membrane-spanning partner protein, EWI-2. The reversed cone-like molecular shape of CD9 generates membrane curvature in the crystalline lipid layers, which explains the CD9 localization in regions with high membrane curvature and its implications in membrane remodeling. The molecular interaction between CD9 and EWI-2 is mainly mediated through the small residues in the transmembrane region and protein/lipid interactions, whereas the fertilization assay revealed the critical involvement of the LEL region in the sperm-egg fusion, indicating the different dependency of each binding domain for other partner proteins.

四跨膜蛋白在从细胞粘附到病毒感染的各种生理过程中都起着至关重要的作用。四跨膜蛋白家族的成员具有四个跨膜结构域和短而大的细胞外环，并与广泛的其他功能蛋白结合以发挥细胞功能。在这里，我们报道了CD9的晶体结构和CD9的低温电子显微镜结构及其单个跨膜伴侣蛋白EWI-2。CD9的倒圆锥状分子形状在结晶脂质层中产生膜曲率，这解释了CD9在具有高膜曲率的区域中的定位及其对膜重构的影响。