Abstract
Since the discovery of mutations in leucine-rich repeat kinase 2 (LRRK2) as an underlying genetic cause for the development of Parkinson's disease (PD) in 2004 (Neuron 44, 601–607; Neuron 44, 595–600), and subsequent efforts to develop LRRK2 kinase inhibitors as a therapy for Parkinson's (Expert Opin. Ther. Targets 21, 751–753), elucidating the atomic resolution structure of LRRK2 has been a major goal of research into this protein. At over 250 kDa, the large size and complicated domain organisation of LRRK2 has made this a highly challenging target for structural biologists, however, a number of recent studies using both in vitro and in situ approaches (Nature 588, 344–349; Cell 182, 1508–1518.e1516; Cell 184, 3519–3527.e3510) have provided important new insights into LRRK2 structure and the complexes formed by this protein.
Highlights
Leucine-rich repeat kinase 2 (LRRK2) has proven to be a protein of interest for a number of reasons
The LRRK2 locus makes a pleiotropic contribution to the risk of Parkinson’s disease with autosomal coding mutations causing Parkinson’s, coding polymorphisms strongly increasing lifetime risk, and non-coding variation more subtly increasing risk as identified by genome-wide population studies [5]. This latter observation is of particular significance, as it implies that the physiological function of LRRK2 may contribute to the disease process in Parkinson’s, the functional consequences of the non-coding variants at the LRRK2 locus are as yet poorly understood [6]
Based on the homology of LRRK2 to the C. tepidum ROCO protein, it has been suggested that LRRK2 instead acts as a G-protein activated by nucleotide-dependent dimerisation (GAD) [24]
Summary
Leucine-rich repeat kinase 2 (LRRK2) has proven to be a protein of interest for a number of reasons. A further structure for the ROC domain of LRRK2 came in 2014 [16]; it was not until 2016 that the first model for full-length LRRK2 was proposed, based upon a 33 Å negative stain electron microscopy reconstruction, a crystal structure for the eponymous leucine-rich repeats isolated from C. tepidum, and mass spectrometry mapping of interactions across the LRRK2 complex [17]. Residues of the protomers of a dimer pair are thought to complement each other’s active site, aiding GTP hydrolysis either by stabilising the protein structure or directly providing catalytic residues [24].
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