About the Project
http://www2.mrc-lmb.cam.ac.uk/groups/dk/DK-lab/Welcome.html
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.
References
Wauer T and Komander D#, “Structure of the human Parkin ligase domain in an autoinhibited state”, EMBO J, (2013) Jul 31;32(15):2099-112.
Wauer T$, Swatek KN$, Wagstaff JL$, Gladkova C, Pruneda JN, Michel MA, Gersch M, Johnson CM, Freund SMV and Komander D# “Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis”, EMBO J (2015) Feb 3; 34(3): 307-25.
Wauer T, Simicek M, Schubert A and Komander D#, “Mechanism of phospho-ubiquitin induced Parkin activation”, Nature (2015) Aug 20; 524(7565): 370-4.
Michel MA, Swatek KN, Hospenthal MK and Komander D#. “Ubiquitin linkage-specific affimers reveal new insights into K6-linked ubiquitin signaling”, Mol Cell, in press
Gersch M, Gladkova C$, Schubert AF$, Michel MA, Maslen SL and Komander D#. “Mechanism and regulation of the Lys6-selective deubiquitinase USP30”, Nat Struct Mol Biol, in press
Gladkova C$, Schubert A$, Jane L. Wagstaff, Pruneda JN, Freund SMV and Komander D#, “An ‘invisible’ ubiquitin conformation is required for efficient phosphorylation by PINK1”, EMBO J, in revision (available on BioRxiv)