Biomedical Engineering Reference
In-Depth Information
are heterodimeric in nature consisting of a common
a
-subunit and a unique
hormone specific
-subunit. Both the subunits in all four hormones are ex-
tensively glycosylated. The integrity of the dimeric form of the hormone is
essential for receptor-binding as individual subunits do not bind to the recep-
tor and are devoid of biological activity. It is held that receptor specificity is
determined by the
b
-subunit can
disrupt receptor binding [127]. In case of hCG, glycosylation in Asn
a
52
has
been demonstrated to be essential for maximization of in vitro bioactivity and
signal transduction [128], while at the same time Asn
a
52
did not show any
activation of FSH receptor by hFSH [129]. In contrast, glycans at Asn
a
52
,and
specifically the terminal SA residues, attenuates in vitro hTSH activity to a
much higher degree than those at Asn
a
78
or Asn
b
23
[130]. Deletion of both
N
-glycans on
b
-subunit, but modifications to either
a
- or
b
a
-subunit resulted in a significant reduction of hTSH bioactivi-
ty [131].
Although structure of glycoprotein hormone receptors and hormone-recep-
tor complexes have not been solved, several models of hormone-receptor inter-
action have been proposed [132, 133]. The molecular mechanism by which
carbohydrates activate the receptor is believed to occur at a post-receptor
binding step [125]. An indirect mechanism involving a conformational change
of the hormone appears more likely than a direct interaction of glycan with the
receptor. Reports on crystal structure of hCG located the glycan at position
Asn
a
52
to be at the dimer interface and within the proposed receptor binding
region [134]. Since the hormone specific
-sub-
unit conformation in a hormone-specific manner, differences in the spatial
orientation of Asn
a
52
glycan may contribute to its differential role in these
hormones. The reported weak thyrotropic activity of hCG has been linked to a
direct interaction with hTSH receptor. This activity of hCG increased upon
desialylation in contrast to a decrease at its native receptor level [135]. Thus, the
observed differences in the role of individual glycans may be related to differen-
ces in receptor structure and/or to receptor dependent differences in receptor-
ligand interactions.
b
-subunit influences common
a
3.7
O
-Glycosylation Functions
The lack of consensus sequence and specific inhibitors for
O
-glycosylation has
hindered studies on the functions of
O
-glycans. The alterations of
O
-glycan
structures often show cancer and inflammatory diseases. There are several
studies indicating that
O
-glycans function as ligands for receptors modulating
such diverse actions as lymphocyte trafficking, sperm-egg binding and tumor
cell adhesion [136, 137]. Free swimming sperm recognize and bind to acidic
glycoprotein zona pellucida (ZP3) on the egg's zona pellucida to initiate fertiliza-
tion process. ZP3 from different mammals consist of a well conserved poly-
peptide that is differentially glycosylated. It has been shown that removal of
O
-glycans from ZP3 destroys its sperm receptor activity, whereas removal of
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