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.
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