Ubiquitin-mediated regulation of mitophagy in Parkinson’s disease
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Protein ubiquitination regulates a large variety of cellular quality control processes including the degradation of damaged mitochondria by mitophagy. This specialised form of autophagy involves the E3 ubiquitin ligase Parkin and the protein kinase PINK1, which together generate a ubiquitin coat on mitochondria that is recognised by the mitophagy machinery. Importantly, mutations in PINK1 and Parkin also lead to hereditary forms of early-onset Parkinson’s disease (PD), providing compelling evidence that mitochondrial quality control is key to PD.
Our lab has significantly contributed to understand mitophagy at the molecular level by determining structures and understanding the biochemistry of key proteins in the pathway (refs 1-5). This has led to numerous insights into mitophagy and its regulation, and suggested new points for interference with mitophagy, and potentially PD.
As a PhD student, you will contribute to our molecular understanding of mitophagy and PD. You will use a plethora of biochemical and structural biology methods (in particular X-ray crystallography, NMR and EM) as well as mass-spectrometry and cell biological techniques to further characterise the complexes of Parkin, PINK1 and USP30 on mitochondria, understand the regulation of these proteins. Your work will contribute to our knowledge of the specialised ubiquitin signals that regulate mitophagy and PD.
Wauer, T. and Komander, D (2013)
Structure of the human Parkin ligase domain in an autoinhibited state
EMBO J; 32(15):2099-112.
Wauer, T., Swatek, K.N., Wagstaff, J.L., Gladkova, C., Pruneda, J.N., Michel, M.A., Gersch, M., Johnson, C.M., Freund, S.M.V. and Komander, D. (2015)
Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis
EMBO J; 34(3): 307-25.
Wauer, T., Simicek, M., Schubert, A. and Komander, D (2015)
Mechanism of phospho-ubiquitin induced Parkin activation
Nature; 524(7565): 370-4.
Michel, M.A., Swatek, K.N., Hospenthal, M.K. and Komander, D
Ubiquitin linkage-specific affimers reveal new insights into K6-linked ubiquitin signaling
Mol Cell, in press
Gersch, M., Gladkova, C., Schubert, A.F., Michel, M.A., Maslen, S.L. and Komander, D.
Mechanism and regulation of the Lys6-selective deubiquitinase USP30
Nat Struct Mol Biol, in press
Gladkova, C., Schubert, A., Wagstaff, J.L., Pruneda, J.N., Freund, S.M.V. and Komander, D
An ‘invisible’ ubiquitin conformation is required for efficient phosphorylation by PINK1
EMBO J, in revision (available on BioRxiv)