X-ray structure of the metastable SEPT14-SEPT7 coiled coil reveals a hendecad region crucial for heterodimerization
X-ray structure of the metastable SEPT14-SEPT7 coiled coil reveals a hendecad region crucial for heterodimerization
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DOI：
10.1107/s2059798323006514
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发表时间：
2023-10-01
影响因子：
2.2
通讯作者：
Garratt，Richard C.
中科院分区：
文献类型：
--
作者：
Cavini，Italo A.;Winter，Ashley J.;Garratt，Richard C.
隔膜蛋白是存在于大多数真核生物中的膜相关的GTP结合蛋白。它们作为细胞骨架的一部分，作为支架和/或扩散屏障发挥重要作用。α-螺旋卷曲螺旋结构域被认为有助于septin组装，并且在人SEPT 6和SEPT 8中观察到的那些形成反平行同源二聚体。这些是不兼容的平行异二聚体组织预期从目前的模型为原丝组装，但他们可以解释通过显微镜观察到的丝间交叉桥。在这里，异二聚体septin卷曲螺旋的第一个结构，SEPT 14和SEPT 7之间;前者是SEPT 6/SEPT 8同源物。这种新的结构是平行的，具有两个长螺旋，所述两个长螺旋相对于它们的序列比对轴向移位一个完整的螺旋圈。该结构还具有不寻常的侧链的钮入孔包装。标准的7个残基（heptad）和不太常见的11个残基（hendecad）重复序列都存在，产生了两个具有相反超螺旋的不同区域，这产生了一个整体直的卷曲螺旋。hendecad区域的一部分是异源二聚化所需的，因此可能是选择性septin识别的关键。这些非常规的序列和结构特征产生亚稳的异源复合物，尽管如此，它仍具有足够的特异性来促进正确的原丝组装。例如，缺乏超螺旋可以促进解链和转变为反平行同源二聚体状态。
Septins are membrane-associated, GTP-binding proteins that are present in most eukaryotes. They polymerize to play important roles as scaffolds and/or diffusion barriers as part of the cytoskeleton. α-Helical coiled-coil domains are believed to contribute to septin assembly, and those observed in both human SEPT6 and SEPT8 form antiparallel homodimers. These are not compatible with their parallel heterodimeric organization expected from the current model for protofilament assembly, but they could explain the interfilament cross-bridges observed by microscopy. Here, the first structure of a heterodimeric septin coiled coil is presented, that between SEPT14 and SEPT7; the former is a SEPT6/SEPT8 homolog. This new structure is parallel, with two long helices that are axially shifted by a full helical turn with reference to their sequence alignment. The structure also has unusual knobs-into-holes packing of side chains. Both standard seven-residue (heptad) and the less common 11-residue (hendecad) repeats are present, creating two distinct regions with opposite supercoiling, which gives rise to an overall straight coiled coil. Part of the hendecad region is required for heterodimerization and therefore may be crucial for selective septin recognition. These unconventional sequences and structural features produce a metastable heterocomplex that nonetheless has enough specificity to promote correct protofilament assembly. For instance, the lack of supercoiling may facilitate unzipping and transitioning to the antiparallel homodimeric state.