Biological membranes are more than just a barrier separating cell cytoplasm from the outside environment. They are highly dynamic and help maintain the integrity and physiological stability of the cells as well as membrane-bound organelles. Membranes also play vital roles in cell-to-cell and intracellular communication.

A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between membrane leaflets.

Endoplasmic Reticulum Membrane

The ER is the starting point of the secretory pathway. It is involved in producing and shuttling proteins and lipids throughout the endomembrane system. It also synthesizes and distributes the membrane-building phospholipids and cholesterol between membrane leaflets. Most cholesterol molecules are quickly transported from the ER to other cell membranes, leaving behind loosely arranged phospholipids in the ER membrane. As a result, the ER membrane is fluid for transporting and inserting newly synthesized lipids and proteins via the secretory pathway. Additionally, the ER assembles the structural phospholipids into bilayers before they bud off as vesicles to fuse with the membrane of the destination organelle.

Membrane Scrambling

The phospholipids can be non-specifically and bidirectionally translocated between the leaflets of the ER membrane by scramblase proteins.

TMEM16K, a resident ER-membrane protein from the TMEM16 scramblase family, is the only identified ER scramblase. Its activity is affected by the length of the phospholipid acyl tails and calcium concentration in the cell. Thus, it works optimally to transport short-chain lipids, characteristic of the thin ER membranes.