Understanding LRRK2: How One Protein's Actions Control Its Own Activity

Let's talk about a protein called LRRK2, which is linked to Parkinson's disease. This protein is like a multitool with seven different parts, including a kinase and a Roc G domain. Even though we know a lot about how it looks, we're still figuring out how it works. Scientists found out that the Roc G domain of LRRK2, like other similar proteins, uses GTP at a rate that matches what's naturally found in cells. They also discovered that a faulty version of LRRK2, called R1441G, makes the protein more efficient. On the other hand, the G2019S version, which is common in Parkinson's, makes the protein less efficient and changes how it uses GTP. This suggests that the kinase part of LRRK2 might be telling the Roc G domain what to do, like a built-in feedback system.A key part of this feedback is a tiny spot on the Roc G domain, called T1343. When this spot is changed to an alanine (like in the T1343A version), the kinase part of LRRK2 becomes more active. This shows that T1343 is important for the feedback system in LRRK2. Interestingly, different Parkinson's-linked mutations in LRRK2 change how the protein uses GTP in different ways. This might help explain why some mutations cause more severe symptoms than others in Parkinson's patients.