12.9
Lipids as Anchors
In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anc…
The three most common types of lipid anchors are prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI anchors.
The prenyl groups are the 15 carbon farnesyl and the 20 carbon geranylgeranyl groups. They bond to cysteine residues at or near the carboxy terminus of proteins.
Saturated 14 carbon myristic acid and the 16 carbon palmitic acid are the most common fatty acyl anchors linked to proteins.
The addition of myristic acid, or myristoylation, happens at a protein's N-terminal glycine residue. Palmitoylation of the proteins can occur at the N- or C- terminal cysteine residue.
Prenylated, myristoylated, and palmitoylated proteins play an essential role in intracellular signaling pathways and protein-protein interactions.
GPI anchors attach to extracellular proteins and contain a core structure of phosphatidylinositol, glucosamine, three mannoses, and phosphoethanolamine.
The phosphoethanolamine bonds to the C-terminal amino acid of the target protein, and the phospholipid inserts itself into the outer layer of the membrane.
This allows GPI anchored proteins to participate in extracellular functions such as cell-cell communication and cell adhesion.
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Q1: What are the three main types of lipid anchors found in eukaryotic membranes?
The three main types are prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol (GPI) anchors. Prenyl and fatty acyl groups anchor proteins on the cytosolic surface of the membrane, while GPI anchors attach proteins to the extracellular side. Each type uses different chemical linkages and serves distinct cellular functions.
Q2: How do prenyl groups attach to proteins and what determines the type of prenylation?
Prenyl groups bond to cysteine residues at or near the protein's carboxy terminus through a CaaX motif. The amino acid at the X position determines whether farnesyl transferase attaches a 15-carbon farnesyl group or geranylgeranyl transferase attaches a 20-carbon geranylgeranyl group. After prenylation, proteases remove the tripeptide, and methylation makes the cysteine hydrophobic.
Q3: What is the difference between myristoylation and palmitoylation?
Myristoylation adds a 14-carbon myristic acid to a protein's N-terminal glycine residue, while palmitoylation adds a 16-carbon palmitic acid to N- or C-terminal cysteine residues. Both are saturated fatty acyl anchors that tether proteins to the membrane. Proteins can use both modifications simultaneously for stronger membrane attachment.
Q4: How do GPI anchors differ from prenyl and fatty acyl anchors in their membrane orientation?
GPI anchors attach to extracellular proteins on the outer membrane layer, whereas prenyl and fatty acyl anchors position proteins on the cytosolic surface. GPI anchors contain a core structure of phosphatidylinositol, glucosamine, three mannoses, and phosphoethanolamine, with the phospholipid inserting into the bilayer and the phosphoethanolamine bonding to the protein's C-terminal amino acid.
Q5: What cellular functions do lipid-anchored proteins perform?
Prenylated, myristoylated, and palmitoylated proteins play essential roles in intracellular signaling pathways and protein-protein interactions. GPI-anchored proteins participate in extracellular functions such as cell-cell communication and cell adhesion. These lipid anchors enable proteins to interact with membrane lipids and other membrane components effectively.
Q6: Why do some proteins require multiple lipid anchors?
Some proteins use more than one lipid anchor to achieve stronger and more stable membrane attachment. For example, cytoplasmic tyrosine kinase is anchored using both myristic and palmitic acid simultaneously. However, GPI-anchored proteins typically do not require additional anchors because their two fatty acyl groups and phosphoethanolamine linkage provide sufficient stabilization.
Q7: What is the CaaX motif and how does it determine prenylation specificity?
The CaaX motif is a recognition sequence at the carboxy-terminal of prenylated proteins where C is cysteine, a represents any aliphatic amino acid, and X is any other amino acid. If X is alanine, serine, methionine, cysteine, or glutamine, farnesyl transferase recognizes it and attaches farnesyl. If X is glutamic acid or leucine, geranyl transferase type I attaches geranylgeranyl instead.