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Membrane Asymmetry

Notes

Membrane Asymmetry

Sections

MEMBRANE COMPONENTS

  • Phospholipids: synthesized on the cytosolic face of the ER
  • Glycolipids
  • Membrane proteins

MEMBRANE SYNTHESIS

  1. Phospholipids are synthesized on the cytosolic face of the ER and glycolipids on the lumenal face of the Golgi apparatus
  2. Vesicles bud from organelles and transport them to cell membrane
  3. Vesicles fuse with cell membrane the lipids they transport retain same orientation unequal distribution of molecules generates curvature
  4. Flippases flip some phospholipids to the extracellular face of bilayer
  5. Glycolipids remain on extracellular face (no flippase action)

TOPOLOGICALLY EQUIVALENT SPACES
Endoplasmic reticulum
Golgi Apparatus
Vesicles
Extracellular space

MEMBRANE LIPIDS DISTRIBUTION

Extracellular layer

  • Phosphatidylcholine: most common, structural
  • Sphingomyelin: less abundant, variable head groups
  • Glycolipids: carbohydrate attached to membrane lipid

Cytosolic layer

  • Phosphatidylethanolamine: small head group that generates curvature
  • Phosphatidylinositol: minor lipid, binds proteins (signal transduction)
  • Phosphatidylserine: binds proteins to membrane
    Variable head groups & fatty acid tail length/saturation

CLINICAL CORRELATION

Apoptosis (programmed cell death)

  • Phosphatidylserine in extracellular leaflet of bilayer is signal for phagocytosis

Full-Length Text

  • Here we will learn about cell membrane asymmetry, which involves the specific orientation of molecules in each layer of the cell membrane.
    • We will also learn how the process of cell membrane synthesis maintains this unique orientation of molecules.
  • First, start a table to summarize the key molecules that contribute to membrane asymmetry.
  • Denote that the key molecules include the following:
    • Phospholipids, which are manufactured in the endoplasmic reticulum.
    • Glycolipids, which obtain their carbohydrate groups in the Golgi apparatus.
    • Membrane proteins, which associate with the bilayer in a diversity of ways.

In this tutorial, we focus on phospholipids and glycolipids.

To begin, let's illustrate the relationships between compartments in the cell.

We'll use purple to represent cytosol and green for non-cytosolic spaces.

  • Draw a cell membrane; leave part of it open for reasons we'll soon see.
  • First draw a large organelle in green to represent the endoplasmic reticulum (the ER) and Golgi apparatus.
  • Next, (in green) show a vesicle bud from the ER and another bud from the Golgi.
  • Then, show each vesicle fuse with the outer cell membrane.
  • Now, label the intracellular space "cytosol."
  • To show these spaces, outline in purple:
    • Endoplasmic reticulum and Golgi apparatus
    • Vesicles
  • Purple represents the cytosolic side of these bilayers.
  • Green represents the non-cytosolic sides.
  • Now, demarcate the cytosolic side of the cellular membrane.
  • Shade the cytosol to distinguish it from the non-cytosolic spaces.
  • Now shade the following luminal spaces to show that they are topologically equivalent with each other and separated from the cytosol:
    • Endoplasmic reticulum and Golgi apparatus
    • Vesicles
  • Importantly, the vesicles maintain their orientation when they bud from the endoplasmic reticulum and the Golgi apparatus.
  • Next, label the region outside the cell membrane as the "extracellular space."
  • Illustrate that the extracellular space is also separated from the cytosol and is topologically equivalent with the lumen of the ER, Golgi and vesicles.

Now, let's illustrate membrane synthesis.

  • Start with the phospholipids, which only add to the cytosolic side of the membrane.
  • Show that enzymes bound to the cytosolic face of the ER membrane synthesize phospholipids, and deposit them on the cytosolic side of the ER bilayer.
  • Show that these newly synthesized phospholipids retain this orientation when they bud into vesicles and also when they fuse with the cell membrane.

Let's see how this unequal distribution of new phospholipids generates curvature in the cell membrane. To do this, let's zoom in on vesicular fusion.

  • First draw a portion of the bilayer with an equal number of phospholipids on each side.
  • Now, add some newly synthesized phospholipids to the cytosolic layer.
    • Recall, new phospholipids retain this orientation from their synthesis in the ER. They only add to the cytosolic side of the membrane.
  • Next, outline the cytosolic and extracellular sides of the bilayer to show that this uneven distribution of phospholipids creates curvature.

How does the whole membrane grow if phospholipids only add to one side?

  • Draw a portion of a bilayer with an equal number of phospholipids in each layer.
  • Show that "flippases" are enzymes that "flip" some of the new phospholipids from the cytosolic layer into the extracellular layer.
  • Outline the cytosolic and extracellular sides of this equally distributed phospholipid bilayer to show that it lacks curvature.
    • Now, the whole membrane grows with the addition of phospholipids, instead of just the cytosolic layer.

Now that we know how new phospholipids add to the bilayer, let's learn how they contribute to membrane asymmetry.

  • Denote that the most common membrane lipids include:
    • Phosphatidylcholine, which is the most common phospholipid and plays a structural role.
    • Sphingomyelin, which has variable head groups.
    • Phosphatidylserine, which binds proteins to the membrane.
    • Phosphatidylethanolamine, which has a small head group that promotes curvature.
    • Phosphatidylinositol, which binds proteins and functions in signal transduction.

Let's draw them, now.

  • Draw a portion of a bilayer and label the extracellular and cytosolic sides.

Now, we will distinguish the phospholipids in each layer of the membrane.

  • Start with the extracellular layer.
  • Indicate that the most abundant phospholipid is phosphatidylcholine.
  • Show that sphingomyelin, while less abundant, is also limited to the extracellular layer.
  • When these phospholipids are newly synthesized, flippases selectively translocate them to the extracellular side of the bilayer.

Now, let's characterize the cytosolic layer.

  • Draw the following lipids in this layer:
    • Phosphatidylserine
    • Phosphatidylethanolamine
    • Phosphatidylinositol
  • Indicate that phosphatidylinositol is sparsely distributed compared to the other lipids.
  • Phospholipids vary not only in their head groups, but also in the length and saturation of their fatty acid tails.
    • We discuss this elsewhere.
  • As a clinical correlation, write that the accumulation of phosphatidylserine in the extracellular layer of a cell membrane is a marker for programmed cell death or "apoptosis."
    • Adjacent cells can recognize the improper orientation of lipids in a bilayer as a signal to eat or "phagocytize" the cell in question.

Now, let's add glycolipids. Return to the diagram of the cell.

  • Draw a glycolipid protruding from the luminal side of the Golgi membrane; enzymes in the Golgi lumen add carbohydrates to membrane lipids.
  • Illustrate that this glycolipid retains its orientation when it buds into a vesicle and when it fuses with the cell membrane.
    • "Flippases" do not move glycolipids, so they always face the extracellular space.
  • Add a glycolipid to the extracellular side of our bilayer diagram.
    • Note that phosphatidylinositol, which has an inositol sugar in its head, is the only exception to the rule for glycolipid distribution.
  • Finally, add cholesterol molecules to both membrane layers, which is present in approximately equal amounts in each layer.
  • Recall that membrane proteins also contribute to cell membrane asymmetry. We discuss protein diversity elsewhere.