Many proteins and protein segments cannot attain a single stable three-dimensional structure under physiological conditions; instead, they adopt multiple interconverting conformational states. Such intrinsically disordered proteins or protein segments are highly abundant across proteomes, and are involved in various effector functions. This review focuses on different aspects of disordered proteins and disordered protein regions, which form the basis of the so-called “Disorder–function paradigm” of proteins. Additionally, various experimental approaches and computational tools used for characterizing disordered regions in proteins are discussed. Finally, the role of disordered proteins in diseases and their utility as potential drug targets are explored.
An amino acid substitution scoring matrix encapsulates the rates at which various amino acid residues in proteins are substituted by other amino acid residues, over time. Database search methods make use of substitution scoring matrices to identify sequences with homologous relationships. However, widely used substitution scoring matrices, such as BLOSUM series, have been developed using aligned blocks that are mostly devoid of disordered regions in proteins. Hence, these substitution-scoring matrices are mostly inappropriate for homology searches involving proteins enriched with disordered regions as the disordered regions have distinct amino acid compositional bias, and therefore expected to have undergone amino acid substitutions that are distinct from those in the ordered regions. We, therefore, developed a novel series of substitution scoring matrices referred to as EDSSMat by exclusively considering the substitution frequencies of amino acids in the disordered regions of the eukaryotic proteins. The newly developed matrices were tested for their ability to detect homologs of proteins enriched with disordered regions by means of SSEARCH tool. The results unequivocally demonstrate that EDSSMat matrices detect more number of homologs than the widely used BLOSUM, PAM and other standard matrices, indicating their utility value for homology searches of intrinsically disordered proteins.
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