Author response: Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels

Proteins are made from long chains of smaller molecules, called amino acids. These chains twist and bend into complex three-dimensional shapes, and sometimes two or more chains, or ‘subunits’, are packed into a protein. These shapes are often held together by hydrogen bonds between some of the amino acids. Moreover, since the shape of a protein defines its function, some proteins must be able to switch between different shapes to function properly. Ion channels are proteins that form pores through cell membranes, allowing ions to flow in and out of the cell. Potassium ion channels, which are found in neurons and heart muscle cells, have four subunits that move to open or close the central pore in response to various signals. The closing of the channels can be ‘fast’ or ‘slow’. When the channels are closed quickly (called fast inactivation), a small part of the protein ‘plugs’ the pore from the inside of the cell. However, the mechanism behind slow inactivation remained obscure. It was thought to involve hydrogen bonds between some of the bulky amino acids that are found at the edge the pore. However, testing this hypothesis—by replacing these amino acids with alternatives that cannot form hydrogen bonds—was tricky because none of the 20 naturally occurring amino acids were alike enough to be suitable replacements. Now, Pless et al. have overcome this limitation by using synthetic amino acids that form hydrogen bonds that are stronger or weaker than those formed by the amino acids they are replacing. The results suggest that two types of hydrogen bond keep the pore open: one is a bond between two amino acids in the same subunit, and the other is an inter-subunit bond between amino acids in neighbouring subunits. Pless et al. suggest that opening the channel causes small movements that gradually weaken, and eventually break, these bonds in one of the four subunits. Specific amino acids within the pore are then free to twist and—via a cascade of similar movements in the other three subunits—block the pore and halt the flow of ions. As such, these networks of hydrogen bonds act as pre-set breaking points allowing channels to close, even in response to continued stimulation. Since regulated potassium channel activity underpins healthy neurons and heart muscles; understanding what controls their inactivation rate may lead to new approaches to tune their activity and treatments for important diseases.

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