Protein function evolution modular proteins

Structure analysis of several proteases involved in blood coagulation and fibrinolysis reveals a diverse, sometimes repetitive, assembly of discrete protein modules (Fig. 9.4) [56]. While these modules represent independent structural units with individual folding pathways, their concerted action contributes to function and specificity in the final protein product. On the genetic level, these individual modules are encoded in separate exons. Over the course of modular protein evolution, new genes are created by duplication, deletion, and rearrangement of these exons. Mechanistically, the exon shuffling actually takes place in the intervening intron sequences (intronic recombination - for further details see [10]). 

Oligomeric states of similarly folded subunits can be very disparate in architecture through evolution and have implications in terms of functions as it has been well exemplified with the hemoglobin family (Royer et al. 2005). The gain of modularity expected by switching from a single domain to multidomains proteins and then to supramolecular assemblies, the fact that components of stable complexes are more conserved than transient ones as well as the fact that essential proteins tend to be subunit of complexes have been discussed from the point of view of evolution (Pereira-Leal et al. 2006 Bomberg-Bauer et al. 2005). 

As expected the PKS for rapamycin showed a Type I organisation strongly reminiscent of the erythromycin PKS, with catalytic activities arranged in modules (Scheme 27) and with sets of modules housed in turn in three multi-modular cassettes designated RAPS 1, RAPS 2 and RAPS 3. RAPS 1 contains modules 1 to 4, RAPS 2 modules 5 to 10, and RAPS 3 modules 11 to 14. The domain structure of the rapamycin PKS may not correspond in every detail to the pattern expected from the proposed structure for the PKS product however. In modules 3 and 6, there appear to be potentially active KR and DH domains which are not required module 3 also contains a potentially active but functionally redundant ER domain. It is possible that the active sites of these extra domains have been inactivated in a way that is not apparent from the primary sequence, and that the now redundant protein residues have still to be edited out by the random processes of evolution. There is also a chance that all these domains are indeed active and that the true rapamycin PKS product is more fully reduced than that shown. Extra post-PKS reoxidations would then be required to reintroduce the oxygen functionality at the relevant sites in the final structure. 

The organization of large proteins into multiple domains Illustrates the principle that complex molecules are built from simpler components. Tike motifs of secondary structure, domains of tertiary structure are Incorporated as modules into different proteins. In Chapter 10 we consider the mechanism by which the gene segments that correspond to domains became shuffled in the course of evolution, resulting in their appearance in many proteins. The modular approach to protein architecture is particularly easy to recognize in large proteins, which tend to be mosaics of different domains and thus can perform different functions simultaneously. 

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