Biology Reference
In-Depth Information
Palmitoylated (16:0) proteins are the
most extensively studied of the lipid-anchored proteins
[32]
. The first member of the pal-
mitoylated class was identified by Braun and Rohn in 1969 in
Ecoli
cell wall
[33]
. Later,
palmitoylation was found in the myelin proteolipid protein (PLP). PLP is the major
protein in the myelin sheath, accounting for ~40% of membrane proteins. PLP is a 4
a
-helix span trans-membrane protein that contains 6 cysteine residues that are thought
to be acylated, primarily with palmitic acid. Other less common acylations involve stearic
acid (18:0) and oleic acid (18:1
6
9
). Acylation of a fatty acid to the sulfur side chain of
cysteine involves reversible formation of a thioester (
Figure 6.11
). In fact being a reversible
fatty acid attachment is perhaps the most important feature of this lipid linkage. Revers-
ibility is in sharp contrast to the myristoylations discussed above and the prenylations
discussed below. Facile palmitoylation and depalmitoylation has the potential to regulate
enzyme activity using acyltransferases and thioesterases, respectively. This is highly
reminiscent of the better recognized enzyme control mechanisms employing phosphory-
lation by kinases and dephosphorylation by phosphatases. Among the large and ever-
growing family of palmitoylated proteins are rhodopsin, band 3 of erythrocytes, and
the lung surfactant proteolipid. Although acylation through a thioester to cystein is the
most important palmitoylation, palmitic acid has also been reported to be O-acylated
to serines and threonines and N-acylated to the
2. PALMITOYLATED LIPID-ANCHORED PROTEINS
-amine side chain of lysine. In Sonic
Hedgehog,palmiticacidisreportedtobeattachedtoanN-terminalcysteineviaan
amide linkage.
ε
c. Prenylated Lipid-Anchored Proteins
Membrane integral proteins can also be lipid-anchored through irreversible thioether link-
ages to very hydrophobic isoprene groups. These proteins are thus termed prenylated
proteins
[34]
. In 1978 Kamiya et al
[35]
discovered the first prenylated protein (actually
a simple 11-amino acid polypeptide), a fungal mating factor. As discussed in Chapter 5, pre-
nylated groups (repeating 5-carbon branched units of 3-methyl-2-buten-1-yl) derive their
name from isoprene. Although it appears that the major function of these prenylated chains
is to anchor the attached protein to the hydrophobic core of membranes, these groups have
an additional, very different and vital role in membranes. Prenyl groups have been shown to
be important for protein
protein binding through specialized prenyl-binding domains
[36]
.
Therefore, prenylated groups are both lipid anchors and are intimately involved in localizing
certain proteins to specific domains, or to specific proteins within the membrane.
Membrane prenylation involves either 15-carbon (3 isoprene) farnesyl or 20-carbon (4
isoprene) geranylgeranyl (see Chapter 4), covalently attached through a thioether to cysteine
residues at or near the C-terminus of proteins (
Figure 6.12
). Once formed, thioethers cannot
be readily removed and so are considered to be permanent attachments. As with myristoy-
lated and palmitoylated proteins, prenylation anchors the protein to the cytoplasmic side
(inner leaflet) of the membrane. Known prenylated proteins include nuclear lamins, Ras
and Ras-associated G proteins, and protein kinases. Since prenylation is essential for the
function of many proteins involved in cellular signaling and trafficking pathways, the
process is becoming a major therapeutic target for multiple diseases. Already there are
more than 20,000 known prenylated proteins, and this number increases daily. Therefore,
it is reasonable to assume that many more prenylated proteins have yet to be discovered.
e
