Structural Basis for E3 ligase-dependent Axonal Degeneration

MYCBP2 is a paradigm-changing ubiquitin E3 ligase with a distinct ubiquitin transfer mechanism (Pao et al. Nature 2018; Mabbitt et al. Nat Chem. Biol. 2020). MYCBP2 ubiquitination activity promotes programmed axon death and is a highly promising drug target for neurological disorders, including neuropathies, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. The functional E3 ligase assembly consists of MYCBP2 and the FBXO45-SKP1 receptor subcomplex. How the complex targets substrates for ubiquitination and how it is regulated to prevent inadvertent neuron death are unknown.

This project will study the FBXO45-SKP1 substrate receptor and its interaction with the MYCBP2 substrate NMNAT2, an axon survival factor. Using biochemical, biophysical and structural techniques, the molecular basis for substrate recognition will be established. The role of the FBXO45-SKP1 subcomplex as a potential regulatory hub will also be explored. In addition, the full-length MYCBP2 complex will be produced and investigated by cryo-EM microscopy. Collectively, this work will afford novel insights into the molecular mechanism of an exemplar non-canonical E3 ligase and provide new strategies for disease treatment.

The post would suit those with research experience in structural biology or biochemistry who are enthusiastic about applying multidisciplinary techniques to a cutting-edge area of research.

Passionate candidates should ideally have recently completed a PhD in structural biology. The position will be a fantastic opportunity for candidates to broaden their skill set by working in a multidisciplinary lab using state-of-the-art technologies. Coupled with this exciting area of biological focus, the project will provide an excellent opportunity for career development, with mentoring support to reach career aspirations. The successful applicants will join an international team in an exciting and interactive environment, equipped to the very highest standards and with generous consumable support.

Your priorities will include:
• design and implement insect cell expression systems to prepare recombinant E3 ligase complexes
• development of enzyme activity assays
• structure determination by cryo-electron microscopy and/or X-ray crystallography
• preparation of data for manuscript publication
• liaise with other lab members and collaborators
• maintenance of meticulous lab records

Whom we are looking for:
Enthusiastic candidates should ideally have recently carried out a PhD working in structural biology or biochemistry and would suit those with the following:
• a passion for ubiquitin research
• experience with enzymology
• experience with structural biology (cryo-EM and/or X-ray crystallography)

This contract is for a fixed term of 3 years with the possibility of extension.
To find out more about the MRC Protein phosphorylation and ubiquitylation unit please visit www.ppu.mrc.ac.uk.

Commitment to DORA
The School of Life Sciences has been fully committed to the principals of the San Francisco Declaration on Research Assessment (DORA) since 2013. In assessing applicants, we consider the scientific quality of their published research papers, but do not take into account where the papers were published and do not consider journal-based metrics, such as Journal Impact Factors.

As an internationally diverse institution, we welcome job applicants from all countries and nationalities. The School of Life Sciences is proud to employ staff from over 40 different nations.

The diversity of our staff and students helps to make the University of Dundee one of the top universities in the UK. Family friendly policies, staff support networks for BME and LGBT staff, membership of Athena Swan and Stonewall, achievement of the Race Equality Charter, as well a full range of disability services, create an enjoyable and inclusive place to work.