The Roc domain of LRRK2 as a hub for protein-protein interactions: a focus on PAK6 and its impact on RAB phosphorylation.

Abstract

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.

• Authors: 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
• Journal: Brain research (Brain Res) Vol. 1778 Pg. 147781 (03 01 2022) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 35016853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• 14-3-3 Proteins
• LRRK2 protein, human
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• PAK6 protein, human
• p21-Activated Kinases
• GTP Phosphohydrolases

Topics

• 14-3-3 Proteins (metabolism)
• GTP Phosphohydrolases (metabolism)
• Humans
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (metabolism)
• Parkinson Disease (metabolism)
• Phosphorylation
• Protein Interaction Domains and Motifs
• p21-Activated Kinases (metabolism)