Chemistry Reference
In-Depth Information
morphology. Part of this function depends on an integrated hyper- network with
highly developed cross-talk to achieve biological signifi cance.
7.4.4.1
Protein Structure and Stability
There is no direct evidence for conformational change in the
O
- fucosylated forms
of Notch, Delta or Jagged compared with the nonglycosylated analogs. Analysis of
single EGF domains from human blood coagulation factor VII showed little evi-
dence for conformational change on fucosylation. However, as the single EGF
domain had limited biological activity, the coordinated action of all EGF domains
in the full length factor VII protein may be important for biological recognition.
This has been proposed as a possible mechanism in the case of the Notch proteins,
where the addition of the
O
-Fuc glycans may mediate conformational change that
is apparent at the whole-molecule level [8]. This concept mirrors other glycosylated
repeat domain proteins such as the mucins, where the relatively weak individual
protein-carbohydrate interactions are enhanced in the form of glycoarray repeat
domains. No data is available for O- Glc glycans.
7.4.4.2
Recognition Phenomena
Interactions involving the
O
-glycans on proteins involved in the Notch pathway
are summarized in Table 7.9 .
7.5
Mucins: A Major Group of
O
- Glycosylated Proteins
The mucin family appears early in metazoan evolution and is a major example of
O
-GalNAc glycosylated proteins. A mucin was the fi rst protein described to be
glycosylated in 1865 (please see Chapter 15.3 for details). In humans at least 19
mucin genes have been identifi ed and encode for mucin monomers that are
heavily
O
-glycosylated. These belong to a family of large glycoproteins that are
either secreted onto mucosal surfaces (for example MUC5AC, MUC5B, MUC2)
or are membrane bound (for example MUC1, MUC4). The abundance of serine
and threonine in the variable number tandem repeat domains ( VNTR ), found in
central mucin monomer regions and not at the
N
- and C - termini, ensures high
O
-glycosylation of these domains, which can carry hundreds of
O
- glycans. More-
over, in secreted mucins the von Willebrand factor C and D domains, at both N-
and C-termini, play an essential role in mucin oligomerization and mucous gel
formation [10]. Membrane-bound mucins contain the VNTR domains, but not the
von Willebrand factor domains (except for MUC4), and have transmembrane and
cytoplasmic domains [11] .
Mucins are essentially part of the mucosal protective barrier, an area rich in
proliferating cells and continuous challenges by the external environment. It is no
wonder that the functions of mucins are diverse, and are apparent in both health
and disease [12]. Apart from the involvement of MUC1 and MUC4 in cell signaling
the secreted mucins are very important for the protection of epithelial surfaces
