We focus on the modifier ubiquitin, a small protein that modifies other proteins in a variety of distinct ways, known as the ‘ubiquitin code’.
Ubiquitination most commonly leads to destruction of the modified protein, but can also change its activation, interactions or localisation. Much of our work aims to enable studies of ubiquitin signals.
A biological focus of the lab are deubiquitinases (DUBs) that remove ubiquitin from proteins. Using structural biology and biophysics, we have unraveled many mechanistic and regulatory principles of how DUBs cleave ubiquitin modifications.
Using preclinical models and in collaboration with human geneticists, we ascribe cellular and physiological function to select enzymes. Finally, in collaboration with industry, we are developing the first enzyme-specific DUB inhibitors, which may become new treatments for cancer and neurodegeneration.
United Kingdom, University of Dundee, DPhil
Germany, University of Bochum, Dipl. Biochem
EMBO member since 2014
Lister Prize Fellow
Gladkova C, Maslen S, Skehel LM, Komander D. Mechanism of Parkin activation by PINK1. Nature. 2018 Jul;559(7714):410-414. Epub 2018 Jun 6. PMID: 29995846
Schubert AF, Gladkova C, Pardon E, Steyaert J, Maslen SL, Komander D. Structure of PINK1 in complex with its substrate ubiquitin. Nature. 2017 Dec 7; 552(7683): 51-56. PMID: 29160309
Turnbull AP, Ioannidis S, Krajewski WW, Pinto-Fernandez A, Martin ACL, Tonkin LM, Townsend EC, Buker SM, Heride C, Lancia Jr. DR, Caravella JR, Toms AV, Charlton TM, Lahdenranta J, Wilker E, Follows BC, Evans NJ, Stead L, Alli C, Zarayskiy ZZ, Talbot AC, Buckmelter AJ, Wang M, McKinnon CL, Saab F , McGouran JF, Century H, Gersch M, Pittman MS, Marshall CG, Raynham TM, Simcox M, Stewart LMD, McLoughlin SB, Escobedo JA, Bair KW, Dinsmore CJ, Hammonds TR, Kim S, Urbé S, Clague MJ, Kessler BM, Komander D. Molecular basis of USP7 inhibition by selective small molecule inhibitors. Nature (2017) Oct 26; 550(7677): 481-486. PMID: 29045389
Gersch M, Gladkova C$, Schubert AF$, Michel MA, Maslen SL, Komander D. Mechanism and regulation of the Lys6-selective deubiquitinase USP30. Nat Struct Mol Biol. 2017 Nov; 24(11): 920-930. PMID: 28945249
Mevissen TET, Kulathu Y, Mulder MPC, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BDM, Akutsu M, El Oualid F, Kawasaki M, Freund SMV, Ovaa H and Komander D. Molecular basis for Lys11-polyubiquitin specificity in Cezanne/OTUD7B. Nature. 2016 Oct 20; 538(7625): 402-405. PMID: 27732584
Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR, McHale D, Maher ER, McKenzie ANJ, Komander D. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell. 2016 Aug 25; 166(5): 1215-1230. Epub Aug 11 PMID: 27523608
Wauer T, Simicek M, Schubert A, Komander D. Mechanism of phospho-ubiquitin induced Parkin activation. Nature. 2015 Aug 20; 524(7565): 370-4. PMID: 26161729
Mevissen TET, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SMV, Ovaa H, Komander D. OTU domain deubiquitinases reveal mechanisms of linkage-specificity and enable ubiquitin chain restriction analysis. Cell. 2013 Jul 3; 154(1): 169-84. PMID: 23827681
Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, Wauer T, Hospenthal MK, Gyrd-Hansen M, Krappmann D, Hofmann K, Komander D. OTULIN antagonizes LUBAC ignalling by specifically hydrolysing Met1-linked polyubiquitin. Cell. 2013 Jun 6; 153(6): 1312-26 PMID: 23746843
A highly studied form of mitophagy – a cellular process that leads to the destruction of damaged mitochondria by autophagy – is regulated by phosphorylated ubiquitin, and uncharacterised Lys6-linked ubiquitin chains. These specialised ubiquitin signals are generated by the ubiquitin kinase PINK1 and the ubiquitin E3 ligase Parkin. Importantly, mutations of PINK1 or Parkin lead to inherited forms of early-onset Parkinson’s disease.
In the past five years, we have provided a detailed molecular description of the ubiquitin signals and enzymes involved in mitophagy. We are now keen to target the system with small molecules, which may be useful to treat neurodegenerative diseases.
Deubiquitinases (or DUBs) are the enzymes that reverse ubiquitin signals, and hence affect all ubiquitin functions. Most importantly, the overproduction of a DUB can lead to the stabilisation of its substrates – a situation highly relevant, for example, with oncogenes, where it has been proposed that small molecule inhibitors of DUBs could initiate the removal of any protein, including so called ‘undruggables’.
We study mechanisms and regulation of DUBs at the structural, biochemical and physiological level. Uncovering the function and substrates of DUBs will be essential to provide new drug targets, and understanding their structure, mechanism and regulation enables drug discovery.
Any science is only as good as the tools available to study it. Our research of unstudied atypical ubiquitin signals and of ubiquitin chain architecture, require the development of new biochemical methods and reagents, which then also give the opportunity to study ubiquitination in unprecedented detail and unveil new biology.
In particular, we have developed methods to study ubiquitin chains using linkage specific deubiquitinases (UbiCREST), and affimers that act similarly to antibodies in detecting understudied ubiquitin chain types.
We work in close collaboration with Dr Andrew Webb to develop new tools to study ubiquitin signals by mass-spectrometry (Ub-clipping).