How PINK1, linked to familial Parkinson’s disease, activates in detail for the first time


In a “world first”, Australian scientists report in detail what happens to the PINK1 protein when activated, helping to eliminate the “confusion” that has surrounded this support protein for cells including dopamine-producing neurons.

Since the mutations of the PINK1 gene that codes for this protein are known to cause certain forms of familial Parkinson’s disease, the discovery could open up new avenues of treatment.

“Biotech and pharmaceutical companies are already considering this protein and pathway as a therapeutic target for Parkinson’s disease, but they’re flying a bit blindly. I think they’ll be really excited to see this amazing new structural information that our team was able to produce ”, David Komander, PhD, professor at the Walter and Eliza Hall Institute for Medical Research (WEHI) and lead author of the study , said in a press release.

The study, “PINK1 activation mechanism, ”Was published in the journal Nature in an unedited (but peer-reviewed) version to “give quick access to its findings”.

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Mitochondria are subcellular structures often referred to as the “powerhouse of the cell” because they are primarily responsible for the production of cellular energy. The PINK1 protein plays an essential role in mitophagy, the process used by cells to recycle damaged or dysfunctional mitochondria and replace them with new ones.

When the PINK1 protein is stabilized on the surface of mitochondria and is activated, it sends signals to other cellular components to initiate mitophagy.

In some forms of Parkinson’s disease, however, mutations in the PINK1 gene lead to a dysfunctional PINK1 protein, which alters mitophagy so that ultimately cells are not able to get enough energy to function as expected. This is believed to be a driving force behind the death of nerve cells in Parkinson’s disease associated with PINK1 mutations, and mitochondrial dysfunction has been strongly linked to Parkinson’s disease in general.

Despite the known role of the PINK1 protein in mitophagy, the details of what actually happens when the protein is activated – in terms of changes at the molecular level – were not clear.

“Numerous papers from labs around the world, including our own, have captured snapshots of the PINK1 protein. However, the differences between these snapshots in some ways fueled confusion about the protein and its structure, ”said Zhong Yan Gan, PhD student at WEHI and the study’s first author.

Gan and his colleagues used a new technique called cryogenic electron microscopy (cryo-EM) to observe the PINK1 protein in motion.

“This is the first time that we have used cryo-EM at WEHI to resolve the structure of small proteins such as PINK1,” said Alisa Glukhova, PhD, professor at WEHI and co-author of the study. “This revolutionary technique has only been available in the past five years, and… is a prime example of how innovative technologies can truly advance research and lead to transformative discoveries,” added Glukhova.

The researchers mainly used cryo-EM to take pictures of the PINK1 protein at different times before, during and after its activation. Then these individual snapshots were “put together” – a kind of stop-motion animation, according to Gan – to demonstrate the series of events by which PINK1 activates.

“We were then able to reconcile why all of those previous structural images were different – these were snapshots taken at different points in time because this protein was activated to perform its function in the cell,” Gan said. “There are tens of thousands of articles on this protein family, but visualizing how this protein comes together and changes in the process of activation is truly a world first.”

A notable finding from this work is that, when activated, PINK1 forms a dimer, a pairing of two proteins connected to each other that work in concert. Specifically, the dimer allows PINK1 proteins to attach phosphate groups – a chemical modification called autophosphorylation which is crucial for their activation.

Formation of the dimer is “essential for turning on or activating the protein to perform its function,” Gan said.

Another notable discovery is that, even when not in its “active” state, the PINK1 protein still retains kinase activity. In other words, its structure suggests that even inactive protein can have biochemical effects on other cellular components.

Scientists noted the need for further research to determine which substance (s) in the cell might interact with PINK1, and the functional consequences of these interactions.

“Our mechanical knowledge will likely aid efforts to exploit PINK1 as a drug target to stimulate mitophagy and treat” Parkinson’s disease, the team concluded.


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