Structure of Human C8 Protein Provides Mechanistic Insight into Membrane Pore Formation by Complement
Structure of Human C8 Protein Provides Mechanistic Insight into Membrane Pore Formation by Complement
复制标题
DOI：
10.1074/jbc.m111.219766
复制
发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Lebioda, Lukasz
中科院分区：
文献类型：
--
作者：
Lovelace, Leslie L.;Cooper, Christopher L.;Lebioda, Lukasz
C8是五种补体蛋白之一，它们聚集在细菌的细胞膜上，形成致命的孔状补体膜攻击复合体(MAC)。MAC由一个C5b、C6、C7和C8分子和12-18个C9分子组成。C8由三个不同的基因亚基组成，即C8α、C8β和C8伽马。C6、C7、C8α、C8β和C9蛋白是同源的，共同组成了MAC蛋白家族。它们都含有N-末端和C-末端模块以及一个中心的40 kDa膜攻击复合体穿孔素(MACPF)结构域，该结构域在形成MAC孔中起着关键作用。在这里，我们报道了从血液中提纯的人C8的2.5A分辨率晶体结构。这是MAC家族成员的第一个结构，也是人类MACPF蛋白的第一个结构。结构表明，C8α和C8β中的模块位于C8的外围，不太可能与靶膜相互作用。C8伽马亚基是Lipocalin蛋白家族的成员，可以结合和运输小的亲脂分子，但没有显示出其假定的配体结合部位。C8α和C8β通过类似22度的旋转而联系在一起，只是沿着旋转轴有一个很小的平移分量。进化争论表明，这两个亚基之间的结合几何形状类似于MAC孔内C9分子的排列。这导致了一个MAC模型，该模型解释了C8-C9和C9-C9的相互作用如何促进MACPF跨膜β-发夹的重折叠和插入形成圆形孔。
C8 is one of five complement proteins that assemble on bacterial membranes to form the lethal pore-like "membrane attack complex" (MAC) of complement. TheMACconsists of one C5b, C6, C7, and C8 and 12-18 molecules of C9. C8 is composed of three genetically distinct subunits, C8 alpha, C8 beta, and C8 gamma. The C6, C7, C8 alpha, C8 beta, and C9 proteins are homologous and together comprise the MAC family of proteins. All contain N- and C-terminal modules and a central 40-kDa membrane attack complex perforin (MACPF) domain that has a key role in forming the MACpore. Here, we report the 2.5A resolution crystal structure of human C8 purified from blood. This is the first structure of a MAC family member and of a human MACPF-containing protein. The structure shows the modules in C8 alpha and C8 beta are located on the periphery of C8 and not likely to interact with the target membrane. The C8 gamma subunit, a member of the lipocalin family of proteins that bind and transport small lipophilic molecules, shows no occupancy of its putative ligand-binding site. C8 alpha and C8 beta are related by a rotation of similar to 22 degrees with only a small translational component along the rotation axis. Evolutionary arguments suggest the geometry of binding between these two subunits is similar to the arrangement of C9 molecules within the MAC pore. This leads to a model of the MAC that explains how C8-C9 and C9-C9 interactions could facilitate refolding and insertion of putative MACPF transmembrane beta-hairpins to form a circular pore.