Helen Walden's Research Group

Pubmed | Biography


Specificity & disease in the Ubiquitin system

How are specific ubiquitin signals produced? How is the right target selected, modified at the right site, at the right time, in the right pathway? The range of signals that can be produced is dizzying, with multiple mono signals, poly signals, and branched signals all part of the cell’s repertoire. However, the mechanistic basis for specificity is still unclear. 

We use a range of techniques, including X-ray crystallography, and two model systems to tackle these questions: 1) an exquisitely specific E3 ligase that targets one site for modification, functions with limited auxiliary enzymes including E2s, and performs only one type of ubiquitination. 2) a broad-spectrum, promiscuous ligase that uses multiple E2s,  to effect multiple signals. Both models are pertinent to human disease, with the specific E3 ligase, FANCL, mutated in patients with Fanconi Anemia, and the broad spectrum ligase, Parkin, mutated in early onset Parkinsonism.

In recent years, we have defined the molecular basis both of specific E2 selection, and how non-selective broad-spectrum E2 use is achieved. We have determined the mechanism of regulation of Parkin via autoinhibition, and established the molecular basis for activation. Our detailed understanding of the specificity in the Fanconi Anemia pathway has allowed us to begin developing small molecules to target the pathway. Our future aims are to define the structural basis for target selection, and specific signal transfer.

Walden Lab Group Photo

People

Connor Arkinson | PhD Student
Viduth Chaugule | Postdoctoral Researcher
Mark Frost | PhD Student
Christel Garcia-Petit | Daphne Jackson Fellow

Selected Publications

Morreale, FE., Bortoluzzi, A., Chaugule, V.K., Arkinson, C., Walden, H., Ciulli, A (2017) Allosteric targeting of the Fanconi anemia E2 Ube2T by fragment screening Journal of Medicinal Chemistry DOI: 10 1021/acs.jmedchem.7b00147
Kumar, A., Chaugule, VK., Condos, TEC., Barber, KR., Johnson, C., Toth, R., Sundaramoorthy, R., Knebel, A., Shaw, GS., Walden, H (2017) Parkin–phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity Nature Structural and Molecular Biology DOI: 10 1038/nsmb.3400
Hodson, C., Purkiss, A., Miles, J. A., Walden, H. (2014) Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection Structure 22 337-44
Kumar, A., Aguirre, J. D., Condos, T. E., Martinez-Torres, R. J., Chaugule, V. K., Toth, R., Sundaramoorthy, R., Mercier, P., Knebel, A., Spratt, D. E., Barber, K. R., Shaw, G. S., Walden, H. (2015) Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis EMBO J 34 2506-21
Chaugule, V. K., Burchell, L., Barber, K. R., Sidhu, A., Leslie, S. J., Shaw, G. S., Walden, H. (2011) Autoregulation of Parkin activity through its ubiquitin-like domain Embo J 30 2853-2867
Cole, AR., Lewis, LPC, Walden, H (2010) The structure of FANCL, the catalytic subunit of the Fanconi Anemia core complex Nature Structural and Molecular Biology 17 294-298