Gibson Team
Biological sequence analysis
Selected LM-rich viral proteins and their cellular partners (Davey, 2010).
Previous and current research
Regulatory decisions during eukaryotic cell signalling are made within large dynamic protein complexes (see Gibson, 2009). Cell regulation is networked, redundant and, above all, cooperative. Decisions are made by in-complex molecular switching. Th e 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 resource ELM 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 fi gure). Th e ELM resource data are now being used by many bioinformatics groups to develop and benchmark LM predictors.
We are now actively hunting for new LM candidates. For example, we recently proposed new candidate KEN boxes, a sequence motif that targets cell cycle proteins for destruction in anaphase, as well as KEPE, a motif of unknown function that is superposed on many sumoylation sites. We look to collaborate with experimental groups undertaking validation experiments.
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. We collaborate with Des Higgins (Dublin) and Julie Thompson (Strasbourg) to maintain and develop the Clustal W and Clustal X programs that are widely used for multiple sequence alignment. We also provide public web servers for Phospho.ELM, a collection of some 42 000 reported phosphorylation sites, and EpiC, a tool to aid in targeting epitopes for antibody selection.
Future projects and goals
We will continue to hunt for regulatory motifs (and may survey individual gene families in depth) and will undertake proteome surveys when we have specifi c questions to answer. Protein interaction networks are anticipated to become increasingly important to our work. 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 the protein architecture tools, especially the unique ELM resource, taking them to a new level of power and applicability. We will apply the tools in the investigation of modular protein function and may deploy them in proteome and protein network analysis pipelines. We are now working to improve the way that bioinformatics standards represent cooperative molecular interactions. Our links to experimental and structural groups should ensure that bioinformatics results feed into experimental analyses of signalling interactions and descriptions of the structures of modular proteins and their complexes, with one focus being regulatory chromatin proteins.