Hokkaido University: Institute for Genetic Medicine

Laboratories

Molecular Interaction

Physiological significance of phospholipid asymmetry in biological membranes.

  • Professor Kazuma TANAKA, Ph.D
  • Assistant Professor Takaharu YAMAMOTO, Ph.D
  • Assistant Professor Tetsuo MIOKA, Ph.D
original page http://www.igm.hokudai.ac.jp/molint/english.html

In most cell membranes, phospholipid compositions are different between two monolayers. Changes in this “phospholipid asymmetry” is involved in various cell functions, including cell polarity, membrane trafficking and organelle functions (Fig. 1). Since phospholipid asymmetry is observed in most cell membranes, its perturbation seems to be involved in many pathological states. Phospholipid asymmetry is generated, maintained, and regulated by lipid translocation or flip-flop, but proteins involved in this flip-flop are largely unknown. Type 4 P-type ATPases or flippases are one such protein and their functions should be elucidated to know physiological significance of phospholipid asymmetry.
Our lab are interested in identification of proteins that regulate phospholipid asymmetry, focusing on elucidating the molecular basis underlying the phospholipid asymmetry. We use yeast Saccharomyces cerevisiae as a model organism, which is amenable to studies in molecular genetics, cell biology, and biochemistry. We are promoting following projects.

1. Role of membrane phospholipid asymmetry in the establishment of cell polarity and vesicular trafficking
We have found that phospholipid flipping by flippases plays an important role in the establishment of cell polarity and vesicular trafficking, especially in vesicle formation on the early endosome in the endocytic recycling pathway (Fig. 2). We will elucidate the molecular mechanism in this flippase-mediated vesicle formation.

2. Identification of new regulators of phospholipid asymmetry and elucidation of their functions
We have found that internal cell membranes exhibit different phospholipid asymmetry. For example, the cytosolic leaflet of the plasma membrane is rich in phosphatidylserine, but those in endoplasmic reticulum and mitochondrion are not. It is suggested that this different phospholipid asymmetry is generated by unknown proteins. Our goal is to identify these proteins to know physiological significance of different phospholipid asymmetry in various organelles.

Fig. 1. Phospholipid asymmetry and phospholipid flippases and their functions
Asymmetric distribution of phospholipids in the plasma membrane is a general feature in eukaryotic cells. Generally, phosphatidylcholine and sphingomyelin are primarily present in the exoplasmic leaflet, and phosphatidylserine and phosphatidylethanolamine are in the cytosolic leaflet. Phospholipid flippases that catalyze the transport of lipid molecules from the exoplasmic to cytosolic leaflet play an important role in establishing and maintaining the phospholipid asymmetry. Changes in phospholipid asymmetry by flippases regulate cell polarity and vesicle trafficking.

Fig. 2. Abnormal membrane structures found in flippase mutant cells
Electron microscopic observation demonstrated that abnormal membrane structures were accumulated in the flippase mutant. These structures, which are not observed in the wild-type, appear to be accumulated early endosomal membranes due to defects in vesicle formation from early endosomes.