Abstract
Large portions of higher eukaryotic proteomes are intrinsically disordered, and abundant evidence suggests that these unstructured regions of proteins are rich in regulatory interaction interfaces. A major class of disordered interaction interfaces are the compact and degenerate modules known as short linear motifs (SLiMs). As a result of the difficulties associated with the experimental identification and validation of SLiMs, our understanding of these modules is limited, advocating the use of computational methods to focus experimental discovery. This article evaluates the use of evolutionary conservation as a discriminatory technique for motif discovery. A statistical framework is introduced to assess the significance of relatively conserved residues, quantifying the likelihood a residue will have a particular level of conservation given the conservation of the surrounding residues. The framework is expanded to assess the significance of groupings of conserved residues, a metric that forms the basis of SLiMPrints (short linear motif fingerprints), a de novo motif discovery tool. SLiMPrints identifies relatively overconstrained proximal groupings of residues within intrinsically disordered regions, indicative of putatively functional motifs. Finally, the human proteome is analysed to create a set of highly conserved putative motif instances, including a novel site on translation initiation factor eIF2A that may regulate translation through binding of eIF4E.
Highlights
During the past decade, there has been increasing focus on the role of intrinsically disordered polypeptide regions in protein functionality [1,2,3,4], resulting in a more complete understanding of the complex wiring of the interactome, and revealing an unexpected level of complexity and cooperativity [5]
We introduce a de novo motif discovery method, SLiMPrints, to identify putative functional motifs in the primary sequence using these relative conservation statistics
The eukaryotic linear motif (ELM) benchmarking data set was used to test the power of the CS, pRLC and the Sigmotif statistics to distinguish ELM and non-ELM residues, and the results are visualized as ROC curve plots (Figure 5A)
Summary
There has been increasing focus on the role of intrinsically disordered polypeptide regions in protein functionality [1,2,3,4], resulting in a more complete understanding of the complex wiring of the interactome, and revealing an unexpected level of complexity and cooperativity [5]. SLiMs have extremely compact protein interaction interfaces [generally encoded by less than four major affinity and specificity determining residues within a stretch of 2–10 residues [9]], and this small footprint promotes high functional density This property facilitates competitive and cooperative binding, allowing complex switches to evolve from a multiplicity of SLiMs, which can be regulated further by the modification state of the protein and local abundance of interaction partners [10,11,12,13]. SLiMs have an inherent evolutionary plasticity, allowing novel instances to evolve de novo, adding functionality and regulatory constraints to proteins, rewiring pathways, a property central to the evolvability of complex systems [15] This evolutionary mechanism promotes redundancy and introduces robustness [16]; motifs often possess weak phenotypes so that malfunctioning motifs are rarely seen to be the primary cause of disease, exceptions exist [17,18,19]. This evolutionary plasticity has drawbacks, as it renders motifs highly susceptible to Nucleic Acids Research, 2012, Vol 40, No 21 10629 mimicry by rapidly evolving pathogens that use them to hijack cellular processes [17,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
