From Protein Structure to Function with Bioinformatics.pdf

5 Structure and Function of Intrinsically Disordered Proteins 1275.4.3.2 Molecular Recognition Elements/FeaturesThese previous observations are in direct connection with the predictability of recognitionelements within IDPs, as demonstrated within the concept of molecularrecognition elements/features (MoREs/MoRFs). In a series of studies, protein-proteincomplexes in PDB in which one partner is shorter than 30 amino acids, the otherlonger (Oldfield et al. 2005b), or one partner is between 10 and 70 amino acids inlength, and the other is a globular protein (Mohan et al. 2006; Vacic et al. 2007),have been analyzed. These analyses have yielded 372 examples of molecular recognitionfeatures (MoRFs), also termed molecular recognition elements (MoREs).MoRFs fall into four basic categories, corresponding to their dominating secondarystructural element, such as α-MoRFs, β-MoRFs, ι-MoRFs, and mixed MoRFs. InMoRFs as a whole, 27% of residues are in the α-helical conformation, 12% are inβ-strands, and approximately 48% are in irregular conformations, with the remaining13% of residues actually missing from the atomic coordinates. The close relationof the concept of MoRFs to PSEs and disorder is demonstrated by that the localstructural preferences of MoRFs are well predictable, exceeding those of globularproteins, and they correlate with disorder in the unbound state (Mohan et al. 2006).This analysis of MoRFs has led to the notion that MoRFs are recognizable bytheir distinguishing pattern of disorder. Usually, a downward spike on disorderscores, in particular with PONDR VL-XT (Iakoucheva et al. 2002), is a strongindication of the presence of a functionally important recognition element. Incombination with sequence motifs, and the functional analysis of proteins whichharbor MoRFs, analysis of these elements provide reasonable hints at thefunction of an IDP/IDR. It is of note that a significant enrichment of MoRFcontainingproteins has been observed in signalling functions (Mohan et al. 2006;Vacic et al. 2007).5.4.3.3 Short Linear Motifs in RecognitionThe analysis of sequences involved in protein-protein interactions has suggestedthat in certain proteins the element of recognition is a short motif of discernibleconservation, often denoted as a “consensus” sequence, such as those involved inmodification by kinases or binding by SH3 domains (Neduvaand Russell 2005).These motifs are evolutionarily variable, and are usually constructed as a few conservedspecificity determinant residues interspersed within largely variable residues,with a typical length between 5 and 25 residues. They are often termed linearmotifs (LMs), also denoted as eukaryotic linear motifs (ELMs) and short linearmotifs (SLiMs). Analysis of LMs collected in the Eukaryotic Linear Motif (ELM)database (Puntervoll et al. 2003) by disorder predictors have shown that LMs andtheir about 20-residue long flanking segments tend to fall into locally disorderedregions (Fuxreiter et al. 2007). Sequence-based prediction of LMs, combined withdisorder prediction and additional functional information may be very useful inpredicting function of IDPs/IDRs.