PROTEIN-PROTEIN INTERACTIONS IN VOLTAGE-GATED POTASSIUM CHANNEL ASSEMBLY AND GA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 我们的研究是检查参与组装和门控电压门控钾通道（Kvs）的蛋白质-蛋白质相互作用。最近的结构生物学研究已经产生了Kv1.2钾通道的结构模型;然而，该结构的许多关键部分分辨率很差或根本没有分辨率。此外，其他Kv家族成员具有Kv1.2通道蛋白上不存在的独特结构基序。最后，辅助亚基蛋白结合核心通道复合物和调节通道功能特性的机制知之甚少。我们的研究旨在更好地阐明Kv通道的这些非解析结构域的功能作用以及辅助蛋白与核心结构域的相互作用以产生天然功能通道复合物。我们的初步研究集中在四个问题：1）在失活和恢复循环过程中，N-末端失活球肽与通道和相关结构的相互作用是什么。2)界面Zn 2+结合位点的存在如何改变胞质T1结构域和非Kv 1型通道的跨膜孔结构域之间的关系。3)DPL辅助蛋白与Kv4.2通道相互作用的机制是什么？4)加速DPP 10a和DPP 6a辅助亚基蛋白失活的机制是什么？在所有这些项目中，我们将离子通道生物物理学，生物化学，结构生物学和分子动力学相结合，对电压门控钾通道的结构和功能产生引人注目的新见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our studies are examining protein-protein interactions involved in the assembly and gating of voltage gated potassium channels (Kvs). Recent structural biology studies have resulted in a structural model of the Kv1.2 potassium channel; however, many key parts of this structure were poorly resolved or not resolved at all. In addition, other Kv family members have distinctive structural motifs that are not present on the Kv1.2 channel protein. Finally, the mechanisms by which auxiliary subunit proteins bind to the core channel complex and regulate channel functional properties are poorly understood. Our studies are aimed at better elucidating the functional roles of these non-resolved domains of Kv channels and the interactions that auxiliary proteins make with the core domain to produce the native functional channel complex. Our initial studies are focusing on four questions: 1) What are the interactions that the N-terminal inactivation ball peptide makes with the channel and associated structures in the course of an inactivation and recovery cycle. 2) How does the presence of an interfacial Zn2+ binding site alter the relationship between the cytoplasmic T1 domain and the transmembrane pore domain of non-Kv1 type channels. 3) What is the mechanism of interaction between the DPL auxiliary protein and the Kv4.2 channel. 4) What is the mechanism for the acceleration of inactivation produced by DPP10a and DPP6a auxiliary subunit proteins. In all these projects, we are combining ion channel biophysics, biochemistry, structural biology and molecular dynamics to produce compelling new insights into the structure and function of voltage gated potassium channels.