Biological sequence analysis
Figure 1: Schematic of cumulative and sequential regulatory switches involving linear motif interactions (see Van Roey et al., 2012)
The Gibson group investigates protein sequence interactions, undertakes computational analyses of macromolecules, and develops tools to enhance sequence analysis research.
Previous and current research
Regulatory decisions during eukaryotic cell signalling are made within large dynamic protein complexes. Cell regulation is networked, redundant and, above all, cooperative. Decisions are made by in-complex molecular switching (see Van Roey et al., 2012, 2013). The deeply misleading ‘kinase cascade’ metaphor needs to be retired and the sooner, the better. Regulatory proteins make remarkable numbers of interactions, with the corollary that they also have highly modular architectures.
We and collaborators develop and deploy the Eukaryotic Linear Motif (ELM) resource for investigating functional sites in modular protein sequences. Linear motifs (LMs) are short functional sites used for the dynamic assembly and regulation of large cellular protein complexes and their characterisation is essential if we are to understand cell signalling. So-called ‘hub’ proteins that make many contacts in interaction networks are being found to have abundant LMs in large segments of IUP (intrinsically unstructured protein segments). Viral proteomes are rich in LMs that are used for hijacking cell systems required for viral production (see figure). We have now created a new resource – called switches.ELM – to capture motif-based regulatory switching mechanisms (see figure). ELM data are now being used by many bioinformatics groups to develop and benchmark LM predictors. We are now actively hunting for new LM candidates and we look to collaborate with groups undertaking validation experiments – for example, in a recent interdisciplinary collaboration we performed bioinformatics analyses of the SxIP motif that is critical for the regulation of microtubule ends.
We also undertake more general computational analyses of biological macromolecules. Where possible, we contribute to multidisciplinary projects involving structural and experimental groups at EMBL and elsewhere. Our collaborators Des Higgins (Dublin) and Julie Thompson (Strasbourg) have released Clustal Omega, a major update to the widely used multiple sequence alignment software. The Lopez team provides a Clustal Omega web server at EMBL-EBI.
Figure 2: Motif-mediated interactions annotated in the ELM resource mapped onto the KEGG human PI3K–Akt signaling pathway (Dinkel et al., 2013)
Future projects and goals
We will continue to hunt for regulatory motifs and we will undertake proteome surveys when we have specific questions to answer. Protein interaction networks are anticipated to become increasingly important to our work (e.g. figure 2). Molecular evolution is also one of the group’s interests, especially when it has practical applications. With our collaborators, we will look to build up protein architecture tools, especially the unique ELM resource, taking them to a new level of power and applicability. We will apply these tools to investigate modular protein function and may deploy them in proteome and protein network analysis pipelines. We are working to improve the way that bioinformatics standards represent cooperative molecular interactions (with the Hermjakob team). As part of the consortia DiGtoP, SyBoSS and SYSCILIA we are looking at interaction networks and systems in stem cells and primary cilia.