Membrane Proteins - An Introduction to Biological Membranes - page 101

d. GPI-Anchored Proteins
While myristoylation, palmitoylation and prenylation all anchor proteins to the cyto-
plasmic side (inside) of membranes, some extracellular proteins are anchored to the outer
surface of cells through the acyl chains of glycosylphosphatidylinositol (GPI) ( Figure 6.13 )
[37,38] . GPI-anchored proteins were discovered at about the same time (1976) by Ikazawa
[39] and by Low [40] . GPI-anchored proteins are not trans-membrane but also cannot be
removed by alkaline carbonate. Therefore, by definition, they are not peripheral proteins.
Their major anchor seems to be through the acyl chains of PI that, without additional electro-
static or hydrophobic interactions, would be very weak. GPI anchored proteins only face
outside and are normally clustered. The attached protein is indirectly linked from its
C-terminal through a phosphoethanolamine, to a glycan (three mannose sugars), to a glucos-
amine and finally to the inositol sugar of PI ( Figure 6.13 ).
GPI-anchored proteins are found in most eukaryotes, but not bacteria. Although GPI-
anchors are not considered to be a common motif of membrane protein structure, there are
some 45 GPI-anchored proteins in man. In yeast, where all GPI proteins are known, only 15
of the 5,790 proteins (about 1 in 400 proteins) have GPI-anchors. GPI-anchored proteins
have a wide variety of essential functions including enzymatic, antigenic, adhesion,
membrane organization, and roles in several receptor-mediated signal transduction path-
ways. Among the better known GPI-anchored proteins are carbonic anhydrase, alkaline phos-
phatase, Thy-1, and BP-3. The GPI-anchored protein can be released from the membrane upon
hydrolysis by phospholipase C, and in fact this is how they were discovered [39,40] . There are
several, mostly rare, human genetic disorders that have been linked to GPI proteins. Perhaps
the best known is Marfan syndrome, whose most famous carrier was reputed in a 1962 theory
to be AbrahamLincoln. Although it has received a great deal of attention, this interesting story
is no longer believed. It is more likely that Lincoln had a different disorder, multiple endocrine
neoplasia type 2B, that causes skeletal features almost identical to Marfan syndrome.
SUMMARY
Soon after Gorter and Grendel proved the existence of lipid bilayers, it became obvious
that proteins were also a component of membranes. It is a protein's amino acid sequence,
not its net content, that locates it to membranes. Hydropathy Plots are used to predict which
segments of a protein cross the membrane. It is not clear how many distinct types of
membrane proteins exist. A first crude approach identifies peripheral (loosely attached to
the membrane surface by electrostatics) and Integral (penetrates into the hydrophobic inte-
rior). Integral proteins span membranes via two major structures, a-helices or b-barrels.
a-Helices can cross the membrane single or multiple times. A very large family of proteins,
including G-protein-coupled receptors, has 7 membrane-spanning a-helices. b-Barrels are
composed of 20 or more b-sheet segments that line a membrane-spanning cylinder. Many
integral proteins are also anchored to the membrane cytoplasmic surface by lipids, primarily
myristyl, palmityl or prenyl groups. Some outer surface proteins are anchored through the
acyl chains of glycosylphosphatidylinositol (GPI). Most membrane surface proteins are
heavily glycosylated.