Structural basis for pH gating of the two-pore domain K+ channel TASK2
Baobin Li
Nature 586, 457–462 (2020). WEB
Structures of TASK2 in the non-conductive closed conformation at pH 6.5 (orange) and conductive open conformation at pH 8.5 (purple).
The lipid bilayer is colored as a pH strip and the closed and open channels are positioned at pH 6.5 and 8.5, respectively.
Baobin and Robert identified two pH sensing gates in TASK2 channels - one extracellular and one intracellular.
They used cryoEM and electrophysiology to learn pH 8.5 both gates are open, and they are mostly closed at pH 6.5. The cryoEM structures identified the amino acids involved in each gate, and they validated the gating model by mutating these residues and recording pH sensitive currents.
Here are a couple of ways to think about this project…
Big picture idea
Just like how you can taste sour things, cells need a way to “taste” their surroundings. We learned about how cells are able to “taste” sour things around them! Cells use nanoscopic sensors and gates to measure what’s going on around them and respond. We show how one of these sensors, a pH gated ion channel called TASK2, works! We did this by taking extremely high resolution (we can see groups of atoms) pictures of the protein with an electron microscope.
Cellular roles
Cells are bioelectric, and use a diverse array of membrane proteins that sense physical and chemical stimuli to translate these stimuli into a singular input: the cellular membrane potential. Our structures of TASK2 at low and high pH show two new types of pH sensor on the extracellular and intracellular sides of the channel. These data clarify how TASK2 can simultaneously sense pH on both sides of the membrane and communicate this pH information to the cell by adjusting the flow of potassium ions to flow through the channel.
Medical relevance
The alkaline-sensitive K2P channel TASK2 is expressed in neurons of the retrotrapezoid nucleus (RTN) in the brainstem contributes to the central chemosensory reflex. They do this by measuring measuring the blood pH, which is a good proxy for the concentration of CO2 in the blood, because CO2 becomes dissolved in the blood as HCO3-, a weak base. TASK2 is thought to measure this proxy for blood CO2, and increase the breathing frequency by making RTN neurons fire more. Mutations of TASK2 are linked to central congenital hypoventilation syndrome. TASK2 channels are also expressed in kidney proximal tubules, where they provide electrogenic feedback that modulates the rate of salt reuptake. K2P family channels are broadly expressed throughout the body including the peripheral and central nervous systems, heart, eyes, kidneys, pancreas and have been implicated in numerous channelopathies over the years.
Structure Highlights
CryoEM structures of TASK2 at low and high pH reveal two novel conformational changes that couple a pH sensing protonatable amino acid (an extracellular arginine or an intracellular lysine) to a conformational change that gates the channel. The structures revealed several new amino acids that participate in the conformation relay between the protonatable side chain and the gate, and verified their participation by generating mutants and observing ablated pH sensitivity. We show that the extracellular pH sensor is coupled to a conformational change at the potassium selectivity filter. The intracellular pH sensor is coupled to a conformational change that pinches closed the intracellular mouth of the channel cavity. It will be interesting to see if other K2P family ion channels like TWIK, TREK and THIK couple new sensors to these gates, or if there are still more gates to be discovered in K2P channels!
Robert Rietmeijer
Interested? Read more about it here!
Structural basis for pH-gating of the two-pore domain K+ channel TASK2.
Li, B*, Rietmeijer, RA* & Brohawn, SG.
Nature 586, 457–462 (2020). WEB