How one membrane protein senses mechanical stress

Chemists (particularly organic chemists) think they’re pretty smart. So see if you can figure out how a membrane embedded ion channel opens due to mechanical stress. The answer is to be found in last week’s Nature (vol. 516 pp. 126 – 130 4 Dec ’14).

As you probably know, membrane embedded proteins get stuck there because they contain multiple alpha helices with mostly hydrophobic amino acids allowing them to snuggle up to the hydrocarbon tails of the lipids making up the lipid bilayer of the biological membrane.

The channel in question is called TRAAK, known to open in response to membrane tension. It conducts potassium ions. The voltage sensitive potassium channels have 24 transmembrane alpha helices, 6 in each of the tetramer proteins comprising it. TRAAK has only 8. As is typical of all ion channels, the helices act like staves on a barrel, shifting slightly to open the pore.

In this case, with little membrane tension, the helices separate slightly permitting a a 10 carbon tail ( CH3 – [ CH2 – CH2 – CH2 ]3 – ) to enter the barrel occluding the pore. Tension on the membrane tends decrease the packing of hydrocarbon tails of the membrane, pulling the plug out of the pore. Neat !! ! ! This is a completely different mechanism than the voltage sensing helix in the 24 transmembrane voltage sensitive potassium channels, and one that no one has predicted despite all their intelligence.

Trigger warning. This paper is by MacKinnon who won the Nobel for his work on potassium channels. He used antibodies to stabilize ion channels so they could be studied by crystallography. Take them out of the membrane and they denature. Why the warning? In his Nobel work he postulated an alpha helical hairpin paddle extending outward from the channel core into the membrane’s lipid interior. It was both hydrophobic and charged, and could move in response to transmembrane voltage changes.

This received vigorous criticism from others, who felt it was an artifact produced by the use of the antibody to stabilize the protein for crystallography.

Why the warning? Because MacKinnnon also used an antibody to stabilize TRAAK.

The whole idea of membrane tension brings up the question of just how strong van der Waals forces really are. Biochemists and molecular biologists tend to think of hydrophobic forces as primarily entropic, pushing hydrophobic parts of a protein together so water would have to exquisitely structure itself to solvate them (e.g. lowering the entropy greatly). Here however, the ‘pull’ if you wish, is due to the mutual attraction of the hydrophobic lipid side chains to each other, which I would imagine is pretty week.

I’m sure that these forces have been measured, and years ago I enjoyed reading about Langmuir’s work putting what was basically soap on a substrate, and forming a two dimensional gas which actually followed something resembling P * Area = n * R * T. So the van der Waals forces have been measured, I just don’t know what they are. Does anyone out there?

Nonetheless, some very slick (physical and organic) chemistry.

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