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J Biol Chem. 2015 Mar 6;290(10):6419-27. doi: 10.1074/jbc.M114.629584. Epub 2015 Jan 21.

Presenilin-like GxGD membrane proteases have dual roles as proteolytic enzymes and ion channels.

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From the Departments of Pharmacology and.
From the Departments of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520


The GxGD proteases function to cleave protein substrates within the membrane. As these proteases contain multiple transmembrane domains typical of ion channels, we examined if GxGD proteases also function as ion channels. We tested the putative dual function by examining two archeobacterial GxGD proteases (PSH and FlaK), with known three-dimensional structures. Both are in the same GxGD family as presenilin, a protein mutated in Alzheimer Disease. Here, we demonstrate that PSH and FlaK form cation channels in lipid bilayers. A mutation that affected the enzymatic activity of FlaK rendered the channel catalytically inactive and altered the ion selectivity, indicating that the ion channel and the catalytic activities are linked. We report that the GxGD proteases, PSH and FlaK, are true "chanzymes" with interdependent ion channel and protease activity conferred by a single structural domain embedded in the membrane, supporting the proposal that higher-order proteases, including presenilin, have channel function.


Alzheimer disease; calcium channel; chanzymes; ion channel; proteases; secretase; γ-secretase

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