From Protein Structure to Function with Bioinformatics.pdf

5 Structure and Function of Intrinsically Disordered Proteins 1155.2 Sequence Features of IDPsAlthough current disorder predictors are based on different principles, the underlyingand unifying feature is that IDPs have “unusual” amino acid composition andsequence that distinguishes them from ordered proteins.5.2.1 The Unusual Amino Acid Composition of IDPsIt has been observed first by Uversky (Uversky et al. 2000) and Dunker and colleagues(Dunker et al. 2001) that the frequency of amino acids in disordered proteinssignificantly differs from that of ordered proteins. The difference does not dependon the method used to establish the structural status of the protein, as they are alwaysdepleted in amino acids of low flexibility indexes (hydrophobic amino acids), andare enriched in amino acids of high flexibility indexes (polar and charged amino acids).The former group (Trp, Cys, Phe, Ile, Tyr, Val, and Leu) is termed order-promoting,whereas the latter (Ala, Arg, Gly, Gln, Ser, Pro, Glu, and Lys) are disorder-promoting(Dunker et al. 2001) amino acids. Similar trends have been found in other studies(Uversky et al. 2000; Tompa 2002), and it is now generally accepted that the twoprimary attributes determining disorder are a low overall level of hydrophobicity,which precludes the formation of a stable globular core, and a high net charge, whichfavours an extended structural state due to electrostatic repulsion.5.2.2 Sequence Patterns of IDPsAll these studies, and the subsequent success of simple prediction algorithms basedon amino acid propensities suggest that the primary determinant of disorder isamino acid composition. The superiority of predictors based on specific sequenceinformation, however, illustrates that the actual sequence of IDPs carries additionalinformation on disorder. Although the low number of experimentally verified disorderedsequences limits studies on such higher-order sequence features, this issuehas already been addressed in a couple of studies. By associating amino acids withproperties such as hydrophobicity, polarity, size, aliphatic/aromatic nature, prolineand charge, simple but statistically overrepresented sequence patterns could beextracted from disordered segments (Lise and Jones 2005). Pro-rich patterns andcharged patterns by either positive or negative residues were found to dominate(e.g. Pos(itive)-Pos-X-Pos, Neg(ative)-Neg-Neg, as well as Glu-Glu-Glu, Lys-X-X-Lys-X-Lys and Pro-X-Pro-X-Pro). Thus, local sequence motifs are associated withdisorder in proteins, a finding which can be rationalized due to the prominence ofrepeat expansion among mechanisms for evolution of IDPs, a procedure whichobviously generates such repetitive sequence motifs (Tompa 2003).