The Roc domain of LRRK2 as a hub for protein-protein interactions
| Autor: | Susanna Cogo, Franz Y. Ho, Elena Tosoni, James E. Tomkins, Isabella Tessari, Lucia Iannotta, Thomas J. Montine, Claudia Manzoni, Patrick A. Lewis, Luigi Bubacco, Marie-Christine Chartier Harlin, Jean-Marc Taymans, Arjan Kortholt, Jeremy Nichols, Laura Cendron, Laura Civiero, Elisa Greggio |
|---|---|
| Přispěvatelé: | Cell Biochemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
LRKK2
General Neuroscience Parkinson's disease protein-protein interactions Parkinson Disease LRRK2 14-3-3 proteins Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 GTP Phosphohydrolases nervous system diseases PAK6 p21-Activated Kinases GTPase Protein-protein interactions Humans Protein Interaction Domains and Motifs Neurology (clinical) Phosphorylation Molecular Biology Developmental Biology |
| Zdroj: | Brain Research, 1778:147781. ELSEVIER SCIENCE BV |
| ISSN: | 0006-8993 |
| Popis: | Leucine-rich repeat kinase 2 (LRRK2) has taken center stage in Parkinson's disease (PD) research as mutations cause familial PD and more common variants increase lifetime risk for disease. One unique feature in LRRK2 is the coexistence of GTPase/Roc (Ras of complex) and kinase catalytic functions, bridged by a COR (C-terminal Of Roc) platform for dimerization. Multiple PD mutations are located within the Roc/GTPase domain and concomitantly lead to defective GTPase activity and augmented kinase activity in cells, supporting a crosstalk between GTPase and kinase domains. In addition, biochemical and structural data highlight the importance of Roc as a molecular switch modulating LRRK2 monomer-to-dimer equilibrium and building the interface for interaction with binding partners. Here we review the effects of PD Roc mutations on LRRK2 function and discuss the importance of Roc as a hub for multiple molecular interactions relevant for the regulation of cytoskeletal dynamics and intracellular trafficking pathways. Among the well-characterized Roc interactors, we focused on the cytoskeletal-related kinase p21-activated kinase 6 (PAK6). We report the affinity between LRRK2-Roc and PAK6 measured by microscale thermophoresis (MST). We further show that PAK6 can modulate LRRK2-mediated phosphorylation of RAB substrates in the presence of LRRK2 wild-type (WT) or the PD G2019S kinase mutant but not when the PD Roc mutation R1441G is expressed. These findings support a mechanism whereby mutations in Roc might affect LRRK2 activity through impaired protein-protein interaction in the cell. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect