... understanding life in molecular detail

Dr Elton Zeqiraj

Ubiquitin, Cell signalling, DUBs


Our lab is interested in ubiquitin structural biology with a main focus on deubiquitinating enzymes (a.k.a. DUBs). The majority of our efforts are dedicated towards understanding how DUBs are activated allosterically, and how they can be inhibited when it is beneficial to do so.

Current major projects include:
  • Understand DUB selectivity and physiological regulation
  • Understand JAMM/MPN domain DUB allosteric activation
  • Indentification of JAMM/MPN domain DUB inhibitors

Ubiquitination of proteins serves as a post-translational signal to regulate virtually all cellular processes through the precise spatial and temporal control of protein stability, activity or localization, and is frequently dysregulated in cancer and other human diseases. The ubiquitin (Ub) processing machinery relies on the actions of E1, E2 and E3 Ub ligases that carry out conjugation of Ub to substrates and the deubiquitinating enzymes (DUBs) that carry out Ub de-conjugation from substrates. A single Ub can be attached to lysine residues on the surface of substrate proteins (this is known as mono-ubiquitination), or conjugated further to lysine residues on the surface of Ub itself, thus leading to poly-Ub chains. Seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) and the free amino terminus (M1) on Ub can be targeted for poly-ubiquitination, and thus eight different Ub chain types can be generated in total, each having different topologies and unique signalling properties.

Ubiquitination is a reversible process and removal of Ub from substrates is carried out by DUBs. DUB actions allow the cell to produce monomeric Ub, recycle Ub from chains and reverse signalling events resulting from ubiquitination. To date, nearly 100 DUBs have been identified in the human genome comprising six major structural families, namely:

   1) Ubiquitin-specific proteases (USPs)

   2) Ubiquitin C-terminal hydrolyases (UCHs)

   3) Machado-Josephin domain proteases (MJDs)

   4) Ovarian tumor proteases (OTUs)

   5) MIU-containing novel DUB family proteases (MINDY)

   6) The Jab1/MPN/Mov34 metalloproteases (JAMMs)    

 

The JAMM/MPN family is unique in using zinc during catalysis, whereas all other DUBs are cysteine proteases.

In our laboratory, we seek to uncover the structural and functional basis by which a set of JAMM/MPN family DUBs select their specific substrates, are regulated by physiological means, and are modulated by small molecules that have the potential to serve as therapeutics.

To read more about our research interests, please visit the laboratory webpage: http://www.personal.leeds.ac.uk/~fbsez/research.html

Detailed research programme                  Close ▲
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Sir Henry Dale and University Academic Fellow (2016 - 2021)

Sir Henry Wellcome Postdoctoral Fellowship (2010-2014); Human Frontiers Postdoctoral Fellowship (2009-2010)

Postdoctoral Fellow (Toronto) 2009 - 2016
Group Leader (Leeds) 2016 - Present

Astbury 8.109
School of Molecular and Cellular Biology
0113 3433079
e.zeqiraj@leeds.ac.uk

http://www.personal.leeds.ac.uk/~fbsez

Selected Publications

  1. E. Zeqiraj, T. Lei, C. Pigott, M. Pillon, N. M. Duffy, D. F. Ceccarelli, A. F. Keszei, K. Lorenzen, I. Kurinov, S. Orlicky, G. D. Gish, A. J. R. Heck, Alba A. Guarné, R. Greenberg and F. Sicheri. Higher order assembly of BRCC36-KIAA0157 is required for DUB activity and biological function. Molecular Cell, 59: 970-983, Sept 2015

  2. E. Zeqiraj, J. Tang, R. W. Hunter, M. Garcia-Rocha, A. Judd, M. Deak, A. von Wilamowitz-Moellendorff, I. Kurinov, J. J. Guinovart, M. Tyers, K. Sakamoto and F. Sicheri. Structural Basis for the Recruitment of Glycogen Synthase by Glycogenin. PNAS, 15;111(28):E2831-40, Jun 2014