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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的研究正在研究参与电压门控钾通道(KVS)组装和门控的蛋白质-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没有得到很好的解析或根本没有解析。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，辅助亚单位蛋白与核心通道复合体结合并调节通道功能特性的机制尚不清楚。我们的研究旨在更好地阐明这些未分解的Kv通道结构域的功能作用，以及辅助蛋白与核心结构域之间的相互作用，从而产生天然的功能通道复合体。我们的初步研究集中在四个问题上：1)在失活和恢复周期过程中，N末端失活球肽与通道及其相关结构发生了什么相互作用。2)界面锌离子结合部位的存在如何改变非KV1型通道胞质T1区和跨膜孔区之间的关系。3)DPL辅助蛋白与Kv4.2通道的相互作用机制是什么。4)DPP10a和DPP6a辅助亚基蛋白加速失活的机制是什么。在所有这些项目中，我们正在结合离子通道生物物理学、生物化学、结构生物学和分子动力学，对电压门控钾通道的结构和功能产生令人信服的新见解。

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.