From Protein Structure to Function with Bioinformatics.pdf

5 Structure and Function of Intrinsically Disordered Proteins 129above, function of IDPs is often is associated with short linear motifs (LMs,ELMs, SLiMs) involved in protein-protein interactions. Because the informationcontent of these short motifs is limited, specialized approaches had to be developedto recognize such regions in proteins. Two such approaches are mentioned here.One approach is DILIMOT (DIscovery of LInear MOTifs (Neduva and Russell2006) ), which exploits the fact that statistical reliability can be tremendouslyimproved if prediction is based on a set of sequences of a common functional feature(an interaction partner or localization), mediated by the short motif likely to bepresent in each of them. From the input sequences, regions unlikely to containinstances of linear motifs (globular domains, signal peptides, trans-membrane andcoiled-coil regions) are removed. Motifs are then uncovered in the remainingsequences by a pattern-matching algorithm, and ranked according to measures ofover-representation and conservation across homologues in related species.Performance is improved by comparing different species and randomization ofsequences. A previous application of the method to high-throughput interactiondatasets of yeast, fly, worm and human sequences resulted in the re-discovery ofmany previously known ELM instances, and also the recognition of novel motifs.For two new putative ELMs, direct binding experiments provided validation of thepredictions – a DxxDxxxD protein phosphatase 1 binding motif with a K dof 22 μMand a VxxxRxYS motif that binds Translin with a K dof 43 μM (Neduva andRussell 2005).Conceptually closely related to MILIMOT is the SliMDisc (Short LinearMotif Discovery) approach (Davey et al. 2006). It is founded on the recognitionthat evidence for the presence of such motifs is much strengthened when the samemotif occurs in several unrelated proteins, evolving by convergence. Finding suchmotifs is hampered by similarity in related proteins that arise by descent. To takethis recognition into account, shared motifs are sought in proteins with little orno primary sequence similarity, from a group of proteins with a common attribute.This latter could be either a shared biological function, sub-cellular location or acommon interaction partner. Motifs discovered by a basic pattern recognitionalgorithm, such as TEIRESIAS, are up-weighted if present in apparently unrelatedsequences and down-weighted if apparently have arisen by common evolutionarydescent. Application of SLiMDisc to a benchmarking set of ELM proteins(Neduva and Russell 2005) has shown a significant improvement in performance.5.5.3 Prediction of MoRFsAs suggested above, MoREs/MoRFs are short functional motifs involved in partnerbinding, which are correlated reasonably well with local disorder of the protein(Mohan et al. 2006; Cheng et al. 2007; Vacic et al. 2007). Their recognition is thusof predictive value with respect to the function of the parent protein. It has beenshown that often such regions can be recognized as irregularities – usually a downwardspike – in disorder patterns obtained by predictors, especially by PONDR VL-XT