Meet Flippase!

Meet P4-type ATPase, better known as Flippase!

Flippase lives and works in the plasma membrane. The plasma membrane is the border between the outside and the inside of the cell made from two layers of phospholipids. (We call the membrane a “phospholipid bilayer.”) Phospholipids have heads that enjoy the water, but their tails hate water. To avoid the water, the phospholipid tails gather in the middle of the membrane.

Diagram of a cell membrane made of two layers. In each layer, phospholipid heads face away from the middle, and phospholipid tails gather in the middle of the membrane.

The outer and inner layers of the plasma membrane have different functions, just like the bricks on the outside of a building serve a different purpose than the sheetrock on the inside. To facilitate different functions, the outer and inner layers are made from different phospholipids in different amounts. The problem is that all phospholipids start out on the inner layer (since they are made on the inside of the cell). Phospholipids that need to go to the outer layer would take way too long to get there on their own–basically forever on the molecular time scale. That’s where Flippase comes in.

A phospholipid flips from one membrane layer to another, requiring its head to pass through the interior past the nonpolar tails.
A phospholipid flips from one membrane layer to the other.

For a phospholipid to flip, its head needs to pass through the middle of the membrane where all the tails are. Molecules that avoid water also avoid things that like the water… like the head of a phospholipid. Flippase allows the head to pass through the middle of the membrane without interacting too much with all of the tails. You can think of it as escorting the head through a place it doesn’t belong.

Flippase uses energy from ATP to do its job (that’s why it’s called an “ATPase”). It is in the P-type ATPase family, and many ion transporters are cousins. This confused scientists at first, because even though Flippase and its cousins all have similar structures, phospholipids are much, much larger than ions. How could Flippase move such a large molecule when its cousins can only move an ion? This question came to be known as “the giant substrate problem.”

Side-by-side models of SERCA,  calcium ion transporter, and ATP8A1, a flippase. They have hardly any structural differences.
A cartoon of a phospholipid next to a calcium ion. The calcium ion is miniscule compared to the size of the phospholipid.

Scientists took a closer look at Flippase in several different stages of its job to help solve the mystery (or at least start solving it). They found that when the energy from ATP is harvested, Flippase holds on to a phosphate ion and opens a gate. A phospholipid can enter the gate head-first and the gate closes once it’s inside. When Flippase lets go of the phosphate ion, the phospholipid inside is allowed to escape to the other side.

Diagram of flippase's mechanism.
1. ATP binds, all helices are stationary.
2. ATP's phosphate is taken by flippase, which tilts the helices to open a gate.
3. The phospholipid enters the gate head-first and the gate closes.
4. Flippase releases the phosphate ion and the phospholipid.
Flippase mechanism

Flippase’s work is super important for keeping our cell’s plasma membrane healthy and functional. Moving phospholipids to the right layer of the membrane allows the membrane to bend correctly, controlling its shape and letting it adapt.

Maintaining different phospholipids on the outside and inside layers also allows the cell to send signals. For example, a phospholipid called phosphatidylserine usually belongs on the inside layer. When Flippase is stopped, it ends up in the outer layer and sends a signal for the cell to die.

Phosphatidylserine in the outer layer of the membrane triggers cell death. Flippase keeps phosphatidylserine in the inner layer.
The phospholipid Phosphatidylserine triggers cell death when it reaches the outer membrane layer.

I’d like to thank my professor for making me research Flippase for his written qualifying exam. I learned a lot and it is because of that research that I can share what I learned with you too. Thank you, Dr. Chapman!

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