The Modular Nature of Proteins

Many proteins do not display global patterns of similarity but instead appear to be mosaics of modular domains (Baron et al 1991 Doolittle and Bork, 1993 Patthy, 

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Protein domains are the common currency of protein structure and function. Protein domains are discrete structural units that fold up to form a compact globular shape. Experiments on protein structure and function have been greatly aided by consideration of the modular nature of proteins. This has allowed very large proteins to be studied. The expression of individual domains has allowed the intractable giant muscle protein titin to be structurally studied (Pfuhl and Pastore, 1995). Protein domains can be found in a variety of contexts, (Fig. 1), in association with a range of unrelated domains and in a variety of orders. Ultimately protein domains are defined at the level of three-dimensional structure however, many protein domains have been described at the level of sequence. The success of sequence-based methods has been demonstrated by numerous confirmations, by elucidation of the three-dimensional structure of the domain. 

The modular design of PKS and NRPS renders them convenient for protein engineering to generate hybrid enzymes that can synthesize a range of natural and unnatural metabolites. By independently manipulating what Cane et al. [143] call the four degrees of freedom in polyketide synthesis variation of chain length, choice of ACP... 

Fig. 5. Modular nature of cellulolytic proteins. The enzyme illustrated (cellobiohydrolase) binds to the cellulose microfibril through the cellulose binding domain while the catalytic domain binds a single cellulose chain at a free end. Arrows representing the active site within the catalytic domain show the ability of cellobiohydrolase to remain bound to the substrate while the hydrolyzed product, cellobiose, is released. This allows the enzyme to progressively hydrolyze cellobiose from cellulose...

The lessons we have learned from physics are of a different nature. The history of physics is replete with examples of the elucidation of connections between what seem to be distinct phenomena and the development of a unifying framework, which, in turn, leads to new observable consequences [13]. Indeed, strong evidence suggests that globular proteins share many common characteristics their ability to fold rapidly and reproducibly in order to create a hydrophobic core, the fact that there seem to be a relatively small number (on the order of a few thousand) of distinct modular folds made up of helices and almost planar sheets, the fact that protein folds are flexible and versatile in order to accomplish the dizzying array of functionalities that these proteins perform, and the unfortunate tendency of proteins to aggregate and form amyloids, which are implicated in human diseases. 

The versatility and modular nature of zinc finger DNA binding proteins, combined with phage display technology, have previously been used to select... 

Many natural products are constrained by macrocyclic motifs, which are often essenhal for natural products to possess the desired biological properties. In the biosynthesis of macrocyclic NRPs and PKs, linear peptides or PKs are often mac-rocyclized by a TE domain located at the C-terminal of multi-modular synthases. For example, in the biosynthesis of the antibiotic tyrocidine A (Tyc A), a linear enzyme-bound decapephde, which is transferred from the last carrier protein (or thiolahon) domain of the Tyc A synthase, is cyclized by an intramolecular Sn2 reachon between the N-terminal amine nucleophile and the C-terminal ester, which is covalently linked to serine residual in the TE domain prior to macro-cyclization (Scheme 7.9) ([35] and references therein). 

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