From Protein Structure to Function with Bioinformatics.pdf

5 Structure and Function of Intrinsically Disordered Proteins 1315.5.4 Combination of Information on Sequence and Disorder:Phosphorylation Sites and CaM Binding MotifsThere are two examples when prediction of short recognition motifs has beenimproved by incorporating information on disorder, namely phosphorylation sitesand calmodulin binding sites (CaMBT) in proteins. Dunker and colleagues havereported (Iakoucheva et al. 2004), by comparing a collection of experimentallydetermined phosphorylation sites (at Ser, Thr or Tyr) to potential sites that are actuallynot phosphorylated, that the regions around phosphorylation sites are significantlyenriched in disorder-promoting amino acids, and depleted in order-promotingamino acids (Dunker et al. 2001). By combining the sets of positive examples andthe corresponding negative examples and considering local disorder, a predictor ofphosphorylation sites could be constructed. DISPHOS (disorder-enhanced phosphorylationpredictor) has an improved accuracy over other phosphorylation-sitepredictor algorithms, such as NetPhos (Blom et al. 1999) and Scansite (Obenaueret al. 2003).The other thoroughly-studied example is the interaction between calmodulin(CaM) and its binding targets, which involves significant flexibility on the side ofboth partners. It is known that CaM usually wraps around a helical bindingpeptide/target (CaMBT) of about 20 amino acids in length (Ikuraand Ames 2006).In a comprehensive analysis it has been pointed out that CaM recognition requiresdisorder of the partner (Radivojac et al. 2006). For example, CaM-dependentenzymes are often stimulated by limited proteolytic digestion (e.g. calcineurin(Manalan and Klee 1983) or cyclic nucleotide phosphodiesterase (Tucker et al.1981) ), which suggests local disorder of the binding site. The inclusion of disorderwas used for developing a predictor of CaMBTs with an improved performance(Radivojac et al. 2006).5.5.5 Flavours of DisorderAs a final word on the predictability of IDP function from sequence, it is pertinentto mention that in several studies it has been suggested IDPs can be clustered interms of their amino acid compositions, and these clusters show some correlationwith function. Whereas the insight gained from these analyses is too limited to beused for the prediction of function, it may be suggestive of important directions offuture research.The trans-activator domains of transcription factors have a strong tendency to bedisordered (Sigler 1988; Minezaki et al. 2006), and they can be classified by theiramino acid composition. Traditionally, transcription factors are distinguished onthe basis of the amino acid preferences of their trans-activator domains, such asacidic, Pro-rich and Gln-rich (Triezenberg 1995). Although the statistical foundationof these differences is practically non-existent, this categorization can be justi-