Ученые раскрыли механизм работы белка, вызывающего болезнь Паркинсона

Weill Cornell Medicine researchers have mapped how a protein tied to Parkinson's disease changes between active and inactive forms, revealing why mutations in different parts of the protein can produce the same harmful overactivity. The medical study examined 16 structures of the protein LRRK2 using electron microscopy and biochemistry. Researchers said the findings could guide drugs that control the protein's molecular switch instead of directly blocking its kinase enzyme, potentially allowing more precise treatment. The work was published Aug. 10 in the journal Cell. It describes a structural platform for drug development rather than a treatment shown to slow or prevent Parkinson's disease in patients. Mutations that make LRRK2 abnormally active are among the most common genetic causes of Parkinson's. Some people without those mutations also show elevated activity, making the protein a leading therapeutic target now being evaluated in at least four clinical trials. A seven-part molecular machine LRRK2 contains seven domains with different jobs. Some help it attach to proteins and structures inside a cell, while two domains carry out enzymatic functions. One domain binds GTP, a molecule used by many proteins as an on-off signal. Such proteins are generally active when bound to GTP and become inactive after converting it to GDP. LRRK2's kinase domain adds phosphate groups to target proteins, changing their behavior inside cells. Elevated levels of those modifications are associated with Parkinson's disease. The protein is present not only in the brain but also in the immune system, lungs and kidneys. Andres Leschziner, a professor of biochemistry and biophysics and co-leader of the study, said that distribution creates a challenge: reducing harmful activity in the brain without disrupting LRRK2's normal functions in other organs. Sixteen structures reveal the switch The team allowed LRRK2 to take different shapes while loaded with GTP, GDP or neither molecule. Comparing 16 structures enabled the researchers to reconstruct the sequence of changes as the protein switches on and off. They found that GDP plays a major role in the inactive state. When GDP is present, LRRK2 forms a compact structure in which key domains block the kinase's active site and prevent it from interacting with target proteins. When GDP is released, the protein shifts into an open shape that exposes the kinase site. Binding GTP can then stabilize that active configuration. Samara Reck-Peterson, chair and professor of biochemistry and biophysics at Weill Cornell and a co-leader of the study, said the structures provide a basis for finding molecules that favor either configuration. Mutations activate LRRK2 in different ways One common Parkinson's-linked mutation sits within the kinase's active site and directly increases enzyme activity. Other common mutations are located far from the kinase but still cause it to become overactive. Using molecular tools that forced LRRK2 into either its active or inactive state, the researchers found that mutations near the GTP-GDP switch do not necessarily make the kinase operate faster. Instead, they keep the protein in its active shape for a longer period. That distinction suggests therapies may need to account for a patient's particular mutation. A drug aimed at the kinase itself may work differently from one designed to stabilize LRRK2's inactive structure. Leschziner said compounds acting on the switch would be considered allosteric drugs. By binding somewhere other than the kinase's active site, they may offer greater precision and fewer side effects than conventional kinase inhibitors, though that possibility still requires drug development and clinical testing. Graduate students Amalia Villagran Suarez and Kathryn Hatch were co-first authors. The project included collaborators from the University of California, San Francisco, and Goethe University in Frankfurt. Funding came from the National Institutes of Health, National Science Foundation, Parkinson's Foundation, Michael J. Fox Foundation, Howard Hughes Medical Institute, LRRK2 Investigative Therapeutics Exchange and the Structural Genomics Consortium, which receives support from public and pharmaceutical-industry partners.