Guilt-by-Association - Functional Insights Gained From Studying the LRRK2 Interactome.

Christian Johannes Gloeckner,Pablo Porras

doi:10.3389/fnins.2020.00485

Abstract

The Parkinson’s disease-associated Leucine-rich repeat kinase 2 (LRRK2) is a complex multi-domain protein belonging to the Roco protein family, a unique group of G-proteins. Variants of this gene are associated with an increased risk of Parkinson’s disease. Besides its well-characterized enzymatic activities, conferred by its GTPase and kinase domains, and a central dimerization domain, it contains four predicted repeat domains, which are, based on their structure, commonly involved in protein-protein interactions (PPIs). In the past decades, tremendous progress has been made in determining comprehensive interactome maps for the human proteome. Knowledge of PPIs has been instrumental in assigning functions to proteins involved in human disease and helped to understand the connectivity between different disease pathways and also significantly contributed to the functional understanding of LRRK2. In addition to an increased kinase activity observed for proteins containing PD-associated variants, various studies helped to establish LRRK2 as a large scaffold protein in the interface between cytoskeletal dynamics and the vesicular transport. This review first discusses a number of specific LRRK2-associated PPIs for which a functional consequence can at least be speculated upon, and then considers the representation of LRRK2 protein interactions in public repositories, providing an outlook on open research questions and challenges in this field.

Highlights

Parkinson’s disease can be divided in two subgroups, the relatively rare familial forms that are caused by mutations in single genes, and idiopathic PD, the cause of which is generally unknown but can be assumed to involve the same pathophysiological pathways and associated molecular networks
Besides its enzymatic core consisting of a Roc (Ras of complex proteins) G-domain and a kinase domain intercepted by the regulatory/dimerization COR (C-terminal of Roc) domain, Leucine-rich repeat kinase 2 (LRRK2) consists of four tandem repeat domains, including the N-terminal Armadillo, Ankyrin and Leucine-rich repeats as well as a C-terminal WD40 fold
To focusing on research aiming at elucidating the function of selected LRRK2 protein-protein interactions (PPIs) in more detail, we provide an update on systematic works by reviewing the current state of the dataset available in the IntAct molecular interaction database (Orchard et al, 2014), which is actively gathering data from various studies, including unbiased interactome-screening approaches

Summary

Introduction

Parkinson’s disease can be divided in two subgroups, the relatively rare familial forms that are caused by mutations in single genes, and idiopathic PD (iPD), the cause of which is generally unknown but can be assumed to involve the same pathophysiological pathways and associated molecular networks. To focusing on research aiming at elucidating the function of selected LRRK2 PPIs in more detail, we provide an update on systematic works by reviewing the current state of the dataset available in the IntAct molecular interaction database (Orchard et al, 2014), which is actively gathering data from various studies, including unbiased interactome-screening approaches.

Results

Conclusion