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Correlated mutation analyses on super‐family alignments reveal functionally important residues
Author(s) -
Kuipers Remko K. P.,
Joosten HenkJan,
Verwiel Eugene,
Paans Sjoerd,
Akerboom Jasper,
van der Oost John,
Leferink Nicole G. H.,
van Berkel Willem J. H.,
Vriend Gert,
Schaap Peter J.
Publication year - 2009
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22374
Subject(s) - mutation , biology , genetics , computational biology , mutase , protein family , sequence alignment , biochemistry , peptide sequence , gene
Correlated mutation analyses (CMA) on multiple sequence alignments are widely used for the prediction of the function of amino acids. The accuracy of CMA‐based predictions is mainly determined by the number of sequences, by their evolutionary distances, and by the quality of the alignments. These criteria are best met in structure‐based sequence alignments of large super‐families. So far, CMA‐techniques have mainly been employed to study the receptor interactions. The present work shows how a novel CMA tool, called Comulator, can be used to determine networks of functionally related residues in enzymes. These analyses provide leads for protein engineering studies that are directed towards modification of enzyme specificity or activity. As proof of concept, Comulator has been applied to four enzyme super‐families: the isocitrate lyase/phoshoenol‐pyruvate mutase super‐family, the hexokinase super‐family, the RmlC‐like cupin super‐family, and the FAD‐linked oxidases super‐family. In each of those cases networks of functionally related residue positions were discovered that upon mutation influenced enzyme specificity and/or activity as predicted. We conclude that CMA is a powerful tool for redesigning enzyme activity and selectivity. Proteins 2009. © 2009 Wiley‐Liss, Inc.