Multi-domain Organization

2 Mucin Structural Properties 2.2.1 Multi-domain Organization 

Mucin polypeptides comprise thousands of amino acid residues organized into different protein domains with specific structural and/or functional properties (Fig. 2.1) (Perez-Vilar and Hill 1999 Dekker et al. 2002). 

NH2-terminal signal peptide (synthesis and translocation into the endoplasmic reticulum) NH2-terminal D-domains (oligomerization/multimerization -interdimer bonds-, N-glycosylation) Partially repeated or non repeated O-Glycosylated sequences (O-glycosylatlon, sulphatlon) 

Repeated O-Glycosylated domains -mucindomains- (O-glycosylatlon, sulphatlon) 

CS-domains (C-mannosylation non-covalent homotypic interchain Interactions) 

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Fig. 2.1 Multi-domain structural organization of gastrointestinal gel-forming mucins. Schematic drawings (not at scale) of the different domains found in gastrointestinal mucins and their roles. Note that while the cysteine-rich domains (D-, CS-, C-, and CK-domains) have a similar length among mucin alleles, the O-glycosylated regions, except in the case of MUC5B, differ in size, a feature not shown in the drawings...

Fig. 2.2 Different levels of structural organization in gel-forming mucins. From the biochemical point of view (a), mucin polypeptides have very complex multi-domain structures and glycosylation patterns and thousands of amino acids per monomer. Moreover, the monomers are assembled into disulfide-linked oligomers/multimers that have contour sizes of several microns.

The limitations of homology modeling also arise when we have insufficient information to build a model for an entire protein. For instance, we may be able to model one or more domains of a multi-domain protein or a multisubunit complex, but it may not be possible to predict the relative organization of the domains or subunits within the full protein. This remains a challenge for further research. And we are of course limited by... 

As previously mentioned, natural fibres present a multi-level organization and consist of several cells formed out of semi-crystalline oriented cellulose micro fibrils. Each microfibril can be considered as a string of cellulose crystallites, linked along the chain axis by amorphous domains (Fig. 19.10) and having a modulus close to the theoretical limit for cellulose. They are biosynthesized by enzymes and deposited in a continuous fashion. A similar structure is reported for chitin, as discussed in Chapter 25. Nanoscale dimensions and impressive mechanical properties make polysaccharide nanocrystals, particularly when occurring as high aspect ratio rod-like nanoparticles, ideal candidates to improve the mechanical properties of the host material. These properties are profitably exploited by Mother Nature. 

Galunic, D. C. Eisenhardt, K. 1996. The evolution of intra-corporate domains divisional charter losses in high-technology, multi-divisional corporations. Organization Science, 7 255-282. 

Phosphopantetheine tethering is a posttranslational modification that takes place on the active site serine of carrier proteins - acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs), also termed thiolation (T) domains - during the biosynthesis of fatty acids (FAs) (use ACPs) (Scheme 23), polyketides (PKs) (use ACPs) (Scheme 24), and nonribosomal peptides (NRPs) (use T domain) (Scheme 25). It is only after the covalent attachment of the 20-A Ppant arm, required for facile transfer of the various building block constituents of the molecules to be formed, that the carrier proteins can interact with the other components of the different multi-modular assembly lines (fatty acid synthases (FASs), polyketide synthases (PKSs), and nonribosomal peptide synthetases (NRPSs)) on which the compounds of interest are assembled. The structural organizations of FASs, PKSs, and NRPSs are analogous and can be divided into three broad classes the types I, II, and III systems. Even though the role of the carrier proteins is the same in all systems, their mode of action differs from one system to another. In the type I systems the carrier proteins usually only interact in cis with domains to which they are physically attached, with the exception of the PPTases and external type II thioesterase (TEII) domains that act in trans. In the type II systems the carrier proteins selectively interact... 

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