Chemistry Reference
In-Depth Information
membrane proteins. This contrasts with other glycoconjugates whose glycan
chains can extend a considerable distance from the plasma membrane, thereby
facilitating
trans
-interactions with other cells or extracellular components.
However, there is evidence that gangliosides can undergo
trans
- interactions in
some instances (for example myelin - associated glycoprotein ( MAG ) or siglec - 4; for
further information on siglecs, a lectin family, please see Chapters 19 and 27.6;
see also below) just as some glycoproteins show
cis
-reactivity. GSLs of the mem-
brane often reside within microdomains termed lipid rafts, which are heteroge-
neous, highly dynamic, cholesterol- and sphingolipid-enriched aggregations that
compartmentalize cellular processes; in addition to GSLs, they sequester numer-
ous glycoprotein receptors in addition to the raft- specifi c glycosylphosphatidylino-
sitol ( GPI ) - anchored proteins (for further information on GPI - anchored proteins,
please see Chapter 9). GM1 often serves as marker for lipid rafts and caveoli,
although its absence from such microdomains has been noted (please see also
Chapter 10.9 ).
GM1 has been perhaps the most widely studied ganglioside in relation to protein
modulatory activities (see Info Box 1). It has the distinction of being one of the
few sialoglycoconjugates whose sialic acid resists hydrolysis by most sialidases in
the intact molecule; this moiety becomes susceptible to sialidase following removal
of terminal galactose and
N
-acetylgalactosamine. The negative charge carried
by the carboxyl of sialic acid is generally required for its modulatory functions.
Such regulatory actions are not limited to the plasma membrane, as seen in the
GM1 activation of a sodium-calcium exchanger in the nuclear membrane (see
Info Box 1). The copresence of GD1a and sialidase in the same membrane pro-
vides a mechanism for regulatory maintenance of GM1 expression at that locus.
In addition to modulation through direct association, GM1 can also infl uence
protein activity 'from a distance', so to speak, through cross-linking in a manner
that triggers downstream signaling. In this way GM1 cross-linking resulted in co-
cross-linking of associated integrin, which in turn caused protein tyrosine kinase
activation with subsequent TRPC5 Ca
2+
channel opening and neurite induction
(see Info Box 1). Cross-linking can also result from carbohydrate recognition by
galectins (for further information on structural and functional aspects of this
interaction, please see Chapters 19 and 25). Other gangliosides were shown to
exert modulatory activities to other proteins. These can be inhibitory as well as
excitatory, as seen in GM3-mediated inhibition of autophosphorylation, and hence
activity, of the insulin receptor. GD3 interacts with mitochondrial proteins causing
cytochrome
c
release and caspase activation in ceramide-induced apoptosis. Such
fi ndings
en toto
have led to the speculation that the great variety of ganglioside
(and other GSL) structures is nature's way of creating modulators that are tailor-
made to react stereospecifi cally with particular membrane proteins.
GSL-protein interaction is well illustrated by the ability of gangliosides to serve
as opportunistic receptors for various bacteria, viruses and toxins. High- affi nity
association of bacterial toxins to certain membrane gangliosides is illustrated in
the tight binding to GM1 by the B-subunits of cholera toxin and
Escherichia coli
enterotoxin (please see Chapter 17.1.3.2) [17]. Such toxins use this attachment
mechanism as a prelude to insertion of their cyclic AMP- elevating A - subunits into
