End-product inhibition of the LRRK2-counteracting PPM1H phosphatase.

ABSTRACT: PPM1H phosphatase reverses Parkinson's disease-associated, Leucine Rich Repeat Kinase 2-mediated, Rab GTPase phosphorylation. We showed previously that PPM1H relies on an N-terminal amphipathic helix for Golgi membrane localization and this helix enables PPM1H to associate with liposomes in vitro; binding to highly curved liposomes activates PPM1H's phosphatase activity. We show here that PPM1H also contains an allosteric binding site for its non-phosphorylated reaction products, Rab8A and Rab10. Microscale thermophoresis revealed that PPM1H binds thio-phosphorylated Rab8A at the active site with a K_D of ~1μM; binding of Rab8A and Rab10 to an alternative site is of similar affinity and is not detected for another LRRK2 substrate, Rab12. Non-phosphorylated Rab8A or Rab10 i

SUBMITTER: Adhikari A 

PROVIDER: S-EPMC12132568 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature