Prof David Komander, Division Head | WEHI Researcher Profile

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About

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.

Education

Publications

Selected publications from Prof David Komander

Gan ZY, Callegari S, Nguyen TN, Kirk NS, Leis A, Lazarou M, Dewson G, Komander D. Interaction of PINK1 with nucleotides and kinetin. Sci Adv. 2024 Jan 19; 10(3):eadj7408. Epub Jan 19. PMID: 38241364.

Calleja DJ, Kuchel N, Lu BGC, Birkinshaw RW, Klemm T, Doerflinger M, Cooney JP, Mackiewicz L, Au AE, Yap YQ, Blackmore TR, Katneni K, Crighton E, Newman J, Jarman KE, Call MJ, Lechtenberg BC, Czabotar PE, Pellegrini M, Charman SA, Lowes KN, Mitchell JP, Nachbur U, Lessene G, Komander D. Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors. Front Chem. 2022 Apr 12; 10:861209. PMID: 35494659.

Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, Geoghegan ND, Rogers KL, Leis A, Dewson G, Glukhova A, Komander D. Activation mechanism of PINK1. Nature. 2022 Feb; 602(7896):328-335. PMID: 34933320.

Klemm T, Ebert G, Calleja DJ, Allison CC, Richardson LW, Bernardini JP, Lu BG, Kuchel NW, Grohmann C, Shibata Y, Gan ZY, Cooney JP, Doerflinger M, Au AE, Blackmore TR, van der Heden van Noort GJ, Geurink PP, Ovaa H, Newman J, Riboldi-Tunnicliffe A, Czabotar PE, Mitchell JP, Feltham R, Lechtenberg BC, Lowes KN, Dewson G, Pellegrini M, Lessene G, Komander D. Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. EMBO J. 2020 Sep 15; 39(18):e106275. PMID: 32845033

Swatek KN, Usher JL, Kueck AF, Gladkova C, Mevissen TET, Pruneda JN, Skern T, Komander D. Insights into ubiquitin chain architecture using Ub-clipping. Nature. 2019 Aug; 572(7770):533-537. PMID: 31413367

Gladkova C, Maslen SL, Skehel JM, Komander D. Mechanism of parkin activation by PINK1. Nature. 2018 Jul; 559(7714):410-414. PMID: 29995846

Schubert AF, Gladkova C, Pardon E, Wagstaff JL, Freund SMV, 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, Heride C, Martin ACL, Tonkin LM, Townsend EC, Buker SM, Lancia DR, Caravella JA, Toms AV, Charlton TM, Lahdenranta J, Wilker E, Follows BC, Evans NJ, Stead L, Alli C, Zarayskiy VV, 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 S, 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, Oualid FE, Kawasaki M, Freund SMV, Ovaa H, Komander D. Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne. 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. 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 TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H, Komander D. OTU 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 signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell. 2013 Jun 6; 153(6):1312-26. PMID: 23746843

Komander D, Rape M. The ubiquitin code. Annu Rev Biochem. 2012 Apr 10; 81:203-29. PMID: 22524316.