1st look at PINK1 structure reveals Parkinson’s clues
Study maps how protein binds to mitochondria, switches on to protect them
Researchers for the first time visualized how PINK1, a protein linked to early-onset Parkinson’s disease, binds to mitochondria and how it’s switched on to protect these energy-producing structures when they’re damaged.
Using a high-resolution microscope to map the structure of the human version of PINK1 bound to damaged mitochondria, the researchers at the Walter and Eliza Hall Institute in Australia gained insight into the protein’s role in Parkinson’s. Understanding how PINK1 works could lead to new treatments that slow or stop the disease’s progression.
“This is a significant milestone for research into Parkinson’s,” David Komander, PhD, division head at the institute and the study’s leader, said in an institute press release. “It is incredible to finally see PINK1 and understand how it binds to mitochondria. Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson’s.”
The study, “Structure of human PINK1 at a mitochondrial TOM-VDAC array,” was published in Science.
Mutations in the PINK1 gene, which codes for the PINK1 protein, are linked to early-onset Parkinson’s, a form of the disease that typically manifests before age 50. Compared with people who develop the disease later in life, those with early-onset Parkinson’s are more likely to have family members with the disease and tend to experience slower disease progression.
Connecting proteins
Problems in how damaged mitochondria are cleared away or function are thought to contribute to Parkinson’s and how fast the disease progresses. While the PINK1 protein is known to help protect mitochondria by tagging them for removal when they’re damaged, how it stays in place inside the damaged mitochondria wasn’t clear.
Using a high-resolution imaging technique called electron microscopy, the researchers took a detailed picture of PINK1 inside damaged mitochondria. They observed that the protein attaches to two important structures, TOM and VDAC, which help proteins move in and out of mitochondria. While TOM is a complex composed of multiple proteins, VDAC has different forms that interact with other proteins.
Two TOM complexes sit on either side of a VDAC pair, with the help of two small proteins (TOM5 and TOM20) keeping everything stable. These proteins also connect to PINK1 kinase.
PINK1 enters mitochondria guided by TOM7 and TOM22, where it’s switched on. These proteins help PINK1 dock to the surface of mitochondria and work correctly.
“This is the first time we’ve seen human PINK1 docked to the surface of damaged mitochondria and it has uncovered a remarkable array of proteins that act as the docking site,” said Sylvie Callegari, PhD, a researcher in Komander’s lab and the study’s first author. “We also saw, for the first time, how mutations present in people with Parkinson’s disease affect human PINK1.”
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