Macromolecular assembly of polycystin-2 intracytosolic C-terminal domain
Macromolecular assembly of polycystin-2 intracytosolic C-terminal domain
复制标题
DOI：
10.1073/pnas.1106766108
复制
发表时间：
2011-06-14
影响因子：
11.1
通讯作者：
Onuchic, Luiz F.
中科院分区：
文献类型：
--
作者：
Ferreira, Frederico M.;Oliveira, Leandro C.;Onuchic, Luiz F.
大约 15% 的常染色体显性多囊肾病病例是由 PKD2 突变引起的。该基因编码多囊蛋白-2，这是一种钙渗透性阳离子通道，其 C 端胞质内尾部 (PC2t) 在其与许多不同蛋白质的相互作用中发挥着重要作用。在本研究中，我们通过一系列生物物理和生化分析全面评估了 PC2t 同寡聚体的大分子组装。我们的研究基于 PC2t 的新定界，表明它能够独立于分子的任何其他部分组装为同四聚体。我们的数据支持在存在和不存在钙的情况下这种四聚体排列。使用改进的基于全原子结构的模型进行的分子动力学模拟支持 PC2t 四聚体组装，以及不同群体在溶液中的处理方式。事实上，模拟表明，得分最高的结构是与四重寡聚状态兼容的结构。这些发现阐明了 PC2t 结构域的结构特性，并有力地支持了 PC2 的同源四聚体组装。
Mutations in PKD2 are responsible for approximately 15% of the autosomal dominant polycystic kidney disease cases. This gene encodes polycystin-2, a calcium-permeable cation channel whose C-terminal intracytosolic tail (PC2t) plays an important role in its interaction with a number of different proteins. In the present study, we have comprehensively evaluated the macromolecular assembly of PC2t homooligomer using a series of biophysical and biochemical analyses. Our studies, based on a new delimitation of PC2t, have revealed that it is capable of assembling as a homotetramer independently of any other portion of the molecule. Our data support this tetrameric arrangement in the presence and absence of calcium. Molecular dynamics simulations performed with a modified all-atoms structure-based model supported the PC2t tetrameric assembly, as well as how different populations are disposed in solution. The simulations demonstrated, indeed, that the best-scored structures are the ones compatible with a fourfold oligomeric state. These findings clarify the structural properties of PC2t domain and strongly support a homotetramer assembly of PC2.