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Dr Sylvie Callegari – Ubiquitin Signalling division

05/02/2025 12:00 pm - 05/02/2025 1:00 pm
Location
Davis Auditorium

WEHI Wednesday Seminar hosted by Professor Grant Dewson
 

Dr Sylvie Callegari

Senior Research Officer – Komander Laboratory, Ubiquitin Signalling division, WEHI

 

Structure of the Parkinson’s disease-linked protein PINK1 on a mitochondrial translocase array

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

 

 

PINK1, a protein linked to Parkinson’s disease, is a ubiquitin kinase that accumulates on the Translocase of the Outer Membrane (TOM complex) of damaged mitochondria. Upon accumulation, PINK1 becomes activated and phosphorylates ubiquitin, generating a unique phospho-ubiquitin signal that triggers mitophagy to remove damaged mitochondria. Enhancing PINK1 activity is a promising strategy for increasing mitochondrial turnover in Parkinson’s patients.

 

One therapeutic approach to boost PINK1 activity, that is currently being explored in the clinic, is to promote its stabilisation on the outer mitochondrial membrane. However, despite decades of research into PINK1 function, the mechanism of PINK1 stabilisation at the TOM complex has remained elusive. Here I will present the cryo-EM structure of stabilised dimeric human PINK1 on the Translocase of the Outer Membrane (TOM) at a resolution of 3.1 Å. The structure uncovers a surprising and unusual arrangement of the TOM complex with the voltage-dependent anion channel, VDAC2 and remarkably, also resolves the PINK1 N-terminus within the TOM40 barrel, providing insights not only into how PINK1 is stabilised, but also into the fundamental process of how mitochondrial import substrates traverse the TOM40 channel. Understanding the mechanisms of PINK1 stabilisation and activation opens up new therapeutic possibilities for using PINK1 to promote the turnover of damaged mitochondria in Parkinson’s disease patients.

 

 

All welcome!

 

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