Chemistry Reference
In-Depth Information
was fi rst observed in 1866 after examination of a man working with chemicals.
The disease was initially called ' intermittent hematinuria ' . In 1928, the term ' par-
oxysmal nocturnal hemoglobinuria' was used. Having herewith illustrated defects
in biosynthesis and mutant cells, we next turn to the function of GPIs.
9.3.3
Function
A wide variety of proteins are tethered by GPI anchors to the extracellular face of
eukaryotic plasma membranes, where they are involved in a number of functions
(Table 9.1 presents examples). In general, GPI-anchored proteins represent a large
class of functionally diverse proteins. GPI proteins have been found in a wide variety
of eukaryotes: mammals (45 in humans), chickens (10), fi sh, rays, sea urchin, fruit
fl ies (5), silk moth, ticks, grasshopper, protozoa, fungi, slime mold, unicellular
green alga, mung bean, even herpes virus (simian surface glycoprotein), but not in
bacteria, and oddly nothing reported from nematode (out of 1208 proteins). Even
prion proteins from all species sequenced so far (from human to chicken) contain
also a C-terminal GPI anchor. Human genetic disorders have been identifi ed in fi ve
GPI proteins other than prion. These include fi brillin - 1 (Marfan ' s syndrome, FBN1
gene), Charcot-Leyden crystals (LPPL gene), alkaline phosphatase (infantile
hypophosphatasia), lipoprotein lipase (chylomicronemia syndrome), glypican- 3
(Simpson-Golabi-Behmel syndrome; for further information on glypicanes, please
see Chapters 11.6.2 and 23.2.3). A defect in a GPI biosynthetic enzyme causes par-
oxysmal nocturnal hemoglobinuria (see above). GPI proteins can be surface anti-
gens, enzymes, adhesion molecules or surface receptors, as seen from Table 9.1 .
GPI-anchored proteins of various microbial pathogens are reported to be immuno-
genic and are suggested to be important virulence factors. In addition, GPI- bound
proteins can display enzymatic properties, playing an active role in cell wall biosyn-
thesis. A summary of their functions is given in Table 9.3 .
Looking at fungi, synthesis of GPI anchors is essential for viability. Effectively,
their cell wall mannoproteins require a GPI anchor so that they can be covalently
incorporated into the cell wall. In intracellular transport, GPI appears to act as an
intracellular signal targeting proteins to the apical surface in polarized cells, since
GPI-anchored proteins are sorted into sphingolipid- and cholesterol- rich micro-
domains, known as lipid rafts, before transport to the membrane surface [12] . Their
localization in raft microdomains may explain the involvement of this class of
proteins in signal transduction processes. Moreover, substantial evidence suggests
that GPI-anchored proteins may interact closely with the bilayer surface so that
their functions may be modulated by the biophysical properties of the membrane.
The presence of the anchor appears to impose conformational restraints, and its
removal may alter the catalytic properties and structure of a GPI- anchored protein.
Furthermore, release of GPI-anchored proteins from the cell surface by specifi c
phospholipases (please see Info Box) may play an important role in regulation of
their surface expression and functional properties. GPI-anchored proteins play an
important role in the biogenesis of the Alzheimer's amyloid
β
- protein, since one
