A Direct Interaction between Leucine-rich Repeat Kinase 2 and Specific beta-Tubulin Isoforms Regulates Tubulin Acetylation

作者：Law Bernard M H; Spain Victoria A; Leinster Veronica H L; Chia Ruth; Beilina Alexandra; Cho Hyun J; Taymans Jean Marc; Urban Mary K; Sancho Rosa M; Ramirez Marian Blanca; Biskup Saskia; Baekelandt Veerle; Cai Huaibin; Cookson Mark R; Berwick Daniel C; Harvey Kirsten^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(2): 895-908.

DOI：10.1074/jbc.M113.507913

Mutations in LRRK2, encoding the multifunctional protein leucine-rich repeat kinase 2 (LRRK2), are a common cause of Parkinson 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 disease. Here, we describe a direct interaction between LRRK2 and beta-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 beta-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 beta-tubulin. Molecular modeling was used to map the interaction surface to the luminal face of microtubule protofibrils in close proximity to the lysine 40 acetylation site in beta-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 disease.

• 出版日期2014-1-10