STRUCTURAL STUDIES OF K CHANNEL COMPLEX

Cornell University, Ithaca NY

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Abstract

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. Kv1 family voltage-dependent potassium channels are highly expressed in heart and important for repolarization of a cardiac action potential. In humans, loss-of-function mutations of Kv1 channels are directly linked to atrial fibrillation. Kv1 channels are modulated by an associated cytosolic beta subunit (Kv[unreadable]), which has a conserved core domain, ~330 amino acids, that resembles an oxidoreductase. Certain Kv[unreadable]s also have a flexible N-terminus, ~70 amino acids, that closes the channel by blocking the ion conduction pore. We have shown that the conserved core of Kv[unreadable] is a functional aldo-keto reductase that utilizes NADPH as cofactor, and that oxidation of the Kv[unreadable]-bound cofactor, either enzymatically by a substrate or non-enzymatically by hydrogen peroxide or NADP+, induces a large increase in channel current. To understand how NADPH oxidation increases channel current, we have mounted a systematic effort to identify regions on Kv1 and Kv[unreadable] that are required for the modulation. Results from these studies have led us to the hypothesis that redox modulation is mediated by the N-terminus of Kv[unreadable]. To further examine the novel mechanism, we propose the following three aims to further examine the mechanism: 1) To identify regions on the N-terminus of Kv[unreadable] that alter the redox modulation; 2) To examine if the N-terminus interacts with the enzymatic core of Kv[unreadable] in a redox dependent manner; 3) To obtain a structure of the N-terminus in complex with the conserved core domain of Kv[unreadable].