Journal Article

DZNE-2026-00683

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes.

Eckert, M. (First author)DZNE* ; Miglionico, P. ; Izzi, F.DZNE* ; De Oliveira Rosa, N. ; Riebenbauer, B.DZNE* ; Ueffing, M. ; Raimondi, F. ; Gloeckner, C. J. (Last author)DZNE*

2026
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s44319-026-00806-4

Abstract: Leucine-rich repeat kinase 2 (LRRK2) not only plays a vital role in familial forms of Parkinson's disease (PD) but also represents a risk factor for idiopathic PD. Its multi-domain architecture enables fine-tuned regulation of its biological function by orchestrating intra- and inter-molecular interactions. Here, we present BioID proximity proteomes of LRRK2 that reveal new interactors, which we further characterize using a novel evolutionary and structural bioinformatics pipeline. Co-evolutionary analysis of the protein-protein interaction network identifies a structural and functional module enriched in cytoskeletal components associated with the centrosome and microtubules. In addition, structural modeling of binary interactions using AlphaFold-Multimer reveals distinct groups of interactors that engage LRRK2 in a manner dependent on specific conformations and epitopes. Furthermore, we identify distinct changes in the LRRK2 proximity proteome that are induced by the type I kinase inhibitor MLi-2 or by co-expression of the LRRK2 upstream effector RAB29. Depending on its activity state and conformation, these protein-protein interactions link LRRK2 to defined cellular sub-compartments, including centriolar satellites and vesicular sub-compartments.

Keyword(s): Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism (MeSH) ; Humans (MeSH) ; Proteomics: methods (MeSH) ; Centrosome: metabolism (MeSH) ; Protein Interaction Maps (MeSH) ; Proteome: metabolism (MeSH) ; Protein Binding (MeSH) ; rab GTP-Binding Proteins: metabolism (MeSH) ; rab GTP-Binding Proteins: genetics (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; LRRK2 protein, human ; Proteome ; rab GTP-Binding Proteins

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Contributing Institute(s):

1. Functional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases (AG Gloeckner)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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