Objective Protein ubiquitination is an important posttranslational modification that regulates virtually all cellular processes. Its versatility arises from the ability of ubiquitin to form eight structurally and functionally distinct polymeric chains. It is clear that all chain types exist in cells. The two chain types that have been studied in detail have distinct, non-overlapping cellular functions. A lack of tools has hindered progress to define roles of the remaining ‘atypical’ ubiquitin chains.The objective of my laboratory is to understand specificity in the ubiquitin system, and to reveal the cellular roles of atypical ubiquitin chains. To achieve this aim, we have to define the cellular machineries that assemble atypical ubiquitin chains specifically (AIM 1). Our recent advances in enzymatic and chemical biology synthesis have made all chain types available, enabling structural and biophysical characterisation of all ubiquitin polymers (AIM 2). We will use the newly generated atypical ubiquitin chains to identify and characterise linkage-specific ubiquitin binding proteins, using mass-spectrometry. This will reveal the receptors of atypical chains in cells, as well as novel ubiquitin binding domains (AIM 3). Access to all linkage types further allows comprehensive analysis of specificity in the ubiquitin system for the first time. We recently discovered that the Ovarian Tumour (OTU) family of deubiquitinating enzymes (DUBs) comprises specific members for each linkage-type. OTU domain DUBs hence represent a great starting point to understand mechanism of linkage specificity and to define substrates modified with atypical chains in cells (AIM 4). Finally, studying cellular functions of linkage-specific OTU DUBs will uncover novel physiological roles of atypical chains (AIM 5).We are only beginning to understand the full potential of ubiquitin in cellular regulation. Our studies on atypical ubiquitination will contribute to these exciting emerging areas of research. Fields of science natural scienceschemical sciencespolymer sciencesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS1 - ERC Starting Grant - Molecular and Structural Biology and Biochemistry Call for proposal ERC-2012-StG_20111109 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution MEDICAL RESEARCH COUNCIL EU contribution € 1 480 285,00 Address 20 Park Crescent W1B 1AL LONDON United Kingdom See on map Activity type Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Administrative Contact Samantha Skehel (Mrs.) Principal investigator David Komander (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all MEDICAL RESEARCH COUNCIL United Kingdom EU contribution € 1 480 285,00 Address 20 Park Crescent W1B 1AL LONDON See on map Activity type Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Administrative Contact Samantha Skehel (Mrs.) Principal investigator David Komander (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data