Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
IRCCS SDN, Via Gianturco 113, 80143 Napoli, Italy.
Biomolecules. 2019 Jul 31;9(8):323. doi: 10.3390/biom9080323.
Several recent investigations have demonstrated that members of the KCTD (Potassium Channel Tetramerization Domain) protein family are involved in fundamental processes. However, the paucity of structural data available on these proteins has frequently prevented the definition of their biochemical role(s). Fortunately, this scenario is rapidly changing as, in very recent years, several crystallographic structures have been reported. Although these investigations have provided very important insights into the function of KCTDs, they have also raised some puzzling issues. One is related to the observation that the BTB (broad-complex, tramtrack, and bric-à-brac) domain of these proteins presents a remarkable structural versatility, being able to adopt a variety of oligomeric states. To gain insights into this intriguing aspect, we performed extensive molecular dynamics simulations on several BTB domains of KCTD proteins in different oligomeric states (monomers, dimers, tetramers, and open/close pentamers). These studies indicate that KCTD-BTB domains are stable in the simulation timescales, even in their monomeric forms. Moreover, simulations also show that the dynamic behavior of open pentameric states is strictly related to their functional roles and that different KCTDs may form stable hetero-oligomers. Molecular dynamics (MD) simulations also provided a dynamic view of the complex formed by KCTD16 and the GABA receptor, whose structure has been recently reported. Finally, simulations carried out on the isolated fragment of the GABA receptor that binds KCTD16 indicate that it is able to assume the local conformation required for the binding to KCTD.
最近的几项研究表明，KCTD（钾通道四聚化结构域）蛋白家族的成员参与了基本过程。然而，由于这些蛋白质的结构数据很少，因此经常无法确定它们的生化作用。幸运的是，随着近年来报道了几个晶体结构，这种情况正在迅速改变。尽管这些研究为 KCTD 的功能提供了非常重要的见解，但它们也提出了一些令人困惑的问题。其中一个问题与观察到这些蛋白质的 BTB（广泛复杂、轨迹和布里克-阿巴斯）结构域具有显著的结构多功能性有关，能够采用多种聚合状态。为了深入了解这一有趣的方面，我们对几种 KCTD 蛋白的 BTB 结构域在不同聚合状态（单体、二聚体、四聚体和开放/闭合五聚体）下进行了广泛的分子动力学模拟。这些研究表明，即使在单体形式下，KCTD-BTB 结构域在模拟时间尺度内也是稳定的。此外，模拟还表明，开放五聚体状态的动态行为与其功能角色密切相关，并且不同的 KCTD 可能形成稳定的异源寡聚体。分子动力学（MD）模拟还提供了 KCTD16 和 GABA 受体形成的复合物的动态视图，其结构最近已经报道。最后，对与 KCTD16 结合的 GABA 受体的分离片段进行的模拟表明，它能够呈现出与 KCTD 结合所需的局部构象。
