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A direct interaction between Leucine-rich Repeat Kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation

Law, BM; Spain, VA; Leinster, VH; Chia, R; Beilina, A; Cho, HJ; Taymans, JM; ... Harvey, K; + view all (2013) A direct interaction between Leucine-rich Repeat Kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation. Journal of Biological Chemistry , 289 (2) pp. 895-908. 10.1074/jbc.M113.507913. Green open access

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Abstract

Mutations in LRRK2, encoding the multifunctional protein leucine-rich repeat kinase 2, are a common cause of Parkinson's disease. LRRK2 has been suggested to influence the cytoskeleton as LRRK2 mutants reduce neurite outgrowth and cause an accumulation of hyperphosphorylated tau. This might cause alterations in the dynamic instability of microtubules suggested to contribute to the pathogenesis of Parkinson's disease. Here, we describe a direct interaction between LRRK2 and β-tubulin. This interaction is conferred by the LRRK2 Roc domain and is disrupted by the familial R1441G mutation and artificial Roc domain mutations that mimic autophosphorylation. LRRK2 selectively interacts with three β-tubulin isoforms: TUBB, TUBB4 and TUBB6, one of which (TUBB4) is mutated in the movement disorder dystonia type 4 (DYT4). Binding specificity is determined by lysine-362 and alanine-364 of β-tubulin. Molecular modelling was used to map the interaction surface to the luminal face of microtubule protofibrils in close proximity to the lysine-40 acetylation site in α-tubulin. This location is predicted to be poorly accessible within mature stabilized microtubules, but exposed in dynamic microtubule populations. Consistent with this finding, endogenous LRRK2 displays a preferential localization to dynamic microtubules within growth cones, rather than adjacent axonal microtubule bundles. This interaction is functionally relevant to microtubule dynamics, as mouse embryonic fibroblasts derived from LRRK2 knockout mice display increased microtubule acetylation. Taken together, our data shed light on the nature of the LRRK2-tubulin interaction, and indicate that alterations in microtubule stability caused by changes in LRRK2 might contribute to the pathogenesis of Parkinson's disease.

Type: Article
Title: A direct interaction between Leucine-rich Repeat Kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M113.507913
Publisher version: http://dx.doi.org/10.1074/jbc.M113.507913
Language: English
Additional information: "This research was originally published in the Journal of Biological Chemistry. Law, BM; Spain, VA; Leinster, VH, et al. A direct interaction between Leucine-rich Repeat Kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation. Journal of Biological Chemistry. 2013; 289(2):pp-pp 895-908. © the American Society for Biochemistry and Molecular Biology." A creative commons Attribution 3.0 Unported (CC BY 3.0) license applies to this article. Which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: GTPase mutation, Lrrk2, Microtubules, Molecular genetics, Parkinson's disease, RocCOR, Tubulin, Cytoskeletal dynamics, Growth cone, Tubulin acetylation
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1417724
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