UCSF

Potassium (K+) channels are membrane-embedded proteins that selectively pass K+ ions in or out of cells in response to a variety of signals, such as membrane potential changes or binding of ligands. In an excitable cell, such as a neuron or cardiac muscle cell, delayed rectifier voltage-gated K+ channels respond to changes in membrane potential to restore the cell membrane to its resting state after an action potential.

In vertebrates, voltage-gated K+ (Kv) channels are tetramers of similar or identical subunits arranged around a central conducting pore. While these channels are primarily gated by membrane potential, their biophysical properties are set by the type of subunits in each tetramer and by interactions with other effector molecules, such as membrane phospholipids, calcium-binding proteins, kinases, and scaffolding proteins. In some cases, discrete intracellular domains control the specific assembly of pore-forming and accessory proteins. However, the molecular mechanisms that direct specific assembly of this wide range of components into a functional K channel complex are incompletely understood.

Chapter 2 of this thesis establishes the atomic-resolution structure of one such assembly domain from a Kv7 family channel (Kv7.4). This study suggests the structural basis for specific assembly properties and binding of scaffolding proteins by other members of the Kv7 channel family. Additional studies in Chapter 3 explore implications of the Kv7.4 assembly domain structure for oligomerization in other subtypes. The biochemical and functional effects of Kv7 mutations designed to disrupt or enhance assembly domain oligomerization further support the critical role for this domain in specific assembly of these channels.