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Biochemistry PhD Seminar: Andrej Paluda

Regulation of ubiquitin transfer by Ark2C​

Modification of proteins with ubiquitin (ubiquitylation) regulates almost all signalling pathways in mammalian cells and its disruption is associated with a range of diseases. Ubiquitylation is a post-translational modification that is executed by a cascade of enzymes called E1, E2, and E3. Specificity is mediated at two levels. The E2 conjugating enzymes determine the function of ubiquitin signal, whereas the E3 ligases specify the substrate for modification by ubiquitin. Among E3s, homologues Arkadia and Ark2C, a RING subclass of E3 ligases, target substrates in multiple pathways including TGF-β and BMP signalling. Activation of Ark-E3 ligase activity is achieved by the recruitment of a secondary, regulatory ubiquitin (UbR). This Ub stabilises the donor ubiquitin (UbD) of the E2∼Ub conjugate for catalysis and enables substrate modification. Additionally, the ability of the Ark-E3s to partner up with several E2s results in formation of distinct polyubiquitin chains that have degradative and non-degradative function. However, the mechanism of the selective E2 recruitment, and E2-specific regulation is unknown.

Structures of Ark2C:E2∼Ub complexes have revealed crucial UbR:UbD contacts that are important for activation. Our structural and biochemical evidence supports, that Ark2C utilises a conserved set of residues to recruit known E2 partners, UbcH5b and Ubc13, but their selective regulation is external to the RING domain. Importantly, we identified (i) a disordered β3 RING loop, that enhances UbR recruitment and regulates UbcH5b activity, and (ii) a conserved N-terminal extension that greatly enhances substrate modification by UbcH5b.

Date Tuesday, 28 April 2020
Time 12:00pm - 1:00pm
Audience All University
Event Category Health Sciences
Event Type Seminar
LocationZoom meeting. Details available from Department secretary

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