Scramblase

Pickings have been slim lately, but here’s a great paper and a puzzle for you chemists out there. Most chemists (and biologists) know what a lipid bilayer is. It’s basically a soap bubble, with water loving (hydrophilic) groups on the outside of both sides of the bilayer, and hydrocarbon chains within. If the hydrocarbon chains are all stretched out the distance between carbons 1 and 3 is 2.66 Angstroms, and you have an 18 carbon fatty acid (stearic acid) it should be 8 * 2.66 + 1.33 Angstroms long (22.6 Angstroms). Double this for the bilayer and you have a thickness of 45 Angstroms. It’s probably less because carbon chains aren’t extended, partially because of entropy and largely because of cholesterol which breaks up any chance of such order (which maybe an important function for it). Sitting on either side of the lipid bilayer are phosphates esterified to one of the 3 hydroxyls of glycerol, with fatty acids of at least 16 – 18 carbons esterified to the other two. Hanging off the phosphates are a variety of things, but mostly serine and choline, forming phosphatidyl serine (PS) and phosphatidyl choline (PC). Here’s a picture — https://en.wikipedia.org/wiki/Lipid_bilayer.

Scramblases are enzymes which move phospholipids from one side of the lipid bilayer essentially randomizing their composition. They undo the action of other enzymes (called flippases believe it or not) which make the lipid composition of the two leaflets of the lipid bilayer rather different. This isn’t trivial, and is behind an elegant mechanism to show scavenger cells that a cell is dead. FLippases work to put phosphatidyl serine (PS) on the side of the lipid bilayer (the leaflet) facing the cytoplasm. This, of course takes energy, and when a cell lacks energy, entropy takes its course and PS appears on the outer leaflet, telling scavenger cells (phagocytes) to eat (phagocytose) the cell.

So how does an enzyme drag phosphatidyl choline (PC) https://en.wikipedia.org/wiki/Phosphatidylcholine or phosphatidyl serine (PC) across the lipid bilayer — scrambling the compositional asymmetry. Can you figure out a mechanism for a membrane protein to do this without looking at Proc. Natl. Acad. Sci. vol. 113 pp. 140149 – 14054 ’16? Chemists think they’re smart, and if you can design a protein to do this you’re smarter than I am because I’ve always wondered (ineffectually) how this was done for a long time.

The authors describe the structure of a fungal scramblase. It functions as a dimer with each subunit containing a hydrophilic groove containing polar and charged amino acid side chains facing the dimer interface. The protein itself does something unusual — it twists the sheet of the membrane, and decreases the thickness of the membrane from 29 to 18 Angstroms (remember the maximum possible thickness of the lipid bilayer was 45 Angstroms, but isn’t that thick for the reasons given above).

Phosphatidyl choline is a zwitterion (e.g. it contains both negative and positive charges although overall electrically neutral). The charges are separated in space forming a dipole. On the cytoplasmic side of the bilayer the scramblase has some amino acid side chains also forming a dipole, and right near the channel formed by the two hydrophilic grooves of the dimer. So it attracts the head group of PC (phosphate plus choline) as one dipole does to another which is then further attracted to the hydrophilic groove entering it — its hydrocarbon tail remains in the lipid part of the membrane. Then another PC joins the fun, pushing PC #1 farther into the groove, so that a chain of PCs fills the groove, wagging their lipid tails behind them (a la Little Bo Peep).

Clever no?

All is not perfect as the model doesn’t explain how phosphatidyl serine (which isn’t a zwitterion) moves across, but it’s an incredible start.

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