Evolutionary Constraints Specifying Protein Folding and Function

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Title: Evolutionary Constraints Specifying Protein Folding and Function
Author: Larson, Christopher
Abstract: Proteins are complex macromolecules that carry out biological functions while under constant mutational load and selective pressure during evolution . Consequently , evolution has generated protein families by exploring the set of sequences able to carry out a particular biological activity , maintaining sequence motifs critical for function while varying the rest of the protein . Statistical coupling analysis of a protein family examines an alignment of such sequences and detects the evolutionarily preserved interresidue interactions critical for the proteins' selective fitness . This set of information has provided a sufficiently detailed description of evolutionary design constraints to allow the design of novel WW domain sequences that fold and function like natural proteins . This work expands the initial investigations , and probes the minimal information content necessary to specify the WW domain fold , as well as the effect of increasing the coupling constraints in the design process . This work also evaluates the ability of coupling information to design larger and more complex protein folds and to specify their biological functions . Experimental expression and characterization of WW domains designed with varying levels of coupling information indicates that incorporating even small amounts of coupling information has a notable impact on these proteins' ability to fold . Moreover , different coupling -based design approaches produce results robust to details of how coupling information is incorporated . Similar experiments with designed PDZ domains and in vivo characterization of designed G -protein coupled receptors show that , to the extent studied , this design approach is successful with these larger and more complex proteins as well . This indicates that the typically sparse matrices of coupling values observed for a protein family capture the core evolutionary constraints on the proteins in sufficient detail to generate even complex proteins with natural -like folds and functions .
URI: http : / /hdl .handle .net /2152 .5 /256
Date: 2007-08-04

Citation

Evolutionary Constraints Specifying Protein Folding and Function. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /256 .

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