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Jack Alexandrovics – Ubiquitin Signalling division

09/08/2024 3:00 pm - 09/08/2024 4:00 pm
Location
Davis Auditorium

WEHI MPhil Completion Seminar hosted by Professor David Komander

Jack Alexandrovics

PhD Student – Komander Laboratory, Ubiquitin Signalling division – Healthy Development & Ageing Theme, WEHI

 

USP16: A ubiquitin sensing rheostat?

 

 

Davis Auditorium

Join via SLIDO enter code #WEHIphdcompletion

Including Q&A session

Followed by refreshments in Tapestry Lounge

 

 

Ubiquitin exists in dynamic equilibrium between its conjugation to substrates and its free mono ‘pool’ form. Proteostasis adapts swiftly to changes in Ubiquitin pool dynamics and evidence suggests rheostatic sensors read Ubiquitin’s concentration via its unconjugated C-terminus and affect gene expression accordingly. USP16, a nucleosome H2AK119 deubiquitinase that regulates multiple genes, contains a Zinc-Finger (Znf) UBP domain that binds the Ubiquitin C-terminus. We hypothesise USP16 acts as a Ubiquitin sensing rheostat, its activity and interaction with the nucleosome regulated by free Ubiquitin via the Znf-UBP domain. 

  

I first characterized the entire family of Znf-UBP domains and used this data to inform the basis of the USP16 rheostat project. Following this, I performed a suite of biochemical assays and was able to develop methods for ‘fine-tuning’ enzymatic activity of USP16 via its regulatory Znf-UBP domain. Additionally, I developed novel mutant ubiquitin’s targeted to specific ubiquitin binding domains, uncovering a novel ubiquitin catalytic mechanism. Finally, I investigated the structural and mechanistic elements of USP16’s interactions with the nucleosome, and how these may be regulated by its Znf-UBP domain. This presentation will argue that USP16’s Znf-UBP domain enhances catalysis and has the potential to regulate the enzyme’s activity, its interaction with the nucleosome, and ultimately gene expression.

 

Jack is a fourth-year PhD student in the Komander Lab, Ubiquitin Signalling Division, supervised by David Komander. His primary research interests are bioengineering and synthetic biology. Outside the lab, he has worked to help develop the inSPIRE program founded the Citizens of Science Parkville Precinct project and revived WEHI’s Inflammatones. He is also a 14-year-old boy who is forced to pilot Ub-Sig-1 by his estranged father and research ubiquitin. Will he be an ark to save mankind from unrestrained proteolysis? Or is he the demon that will destroy us all? Find out on August 9th at 3 pm at the best PhD completion seminar taking place that week.

 

All welcome!

 

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