Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes

The Leucine-rich repeat kinase 2 (LRRK2) not only plays a vital role in familial forms of Parkinson’s disease (PD) but is also considered as a risk factor for idiopathic PD. Its multi-domain architecture enables a fine-tuned regulation of its biological function by orchestrating intra- and inter-molecular interactions. Here, we present BioID proximity proteomes of LRRK2 revealing new interactors, which we further characterized by a novel evolutionary and structural bioinformatics pipeline. Co-evolutionary analysis of the protein-protein interaction network identified a structural and functional module enriched in cytoskeletal components linked to the centrosome and microtubules. Furthermore, structural modelling of binary interactions via AlphaFold-multimer revealed distinct groups of interactors engaging with LRRK2 dependent on specific conformations and epitopes. Furthermore, we identified distinct changes in the LRRK2 proximity proteome induced by the type I kinase inhibitor MLi-2 or by co-expression of the LRRK2 upstream effector RAB29. Dependent on its state of activity and conformation, these protein-protein interactions link LRRK2 to defined cellular sub-compartments, including centriolar satellites as well as vesicular sub-compartments.