title: A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.
abstract: 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 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 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 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 knock-out 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.
authors.affiliation: From the Department of Pharmacology, UCL School of Pharmacy, University College London 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
authors.forename: Bernard M H
authors.initials: BM
authors.lastname: Law
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Spain
authors.forename: Veronica H L
authors.initials: VH
authors.lastname: Leinster
authors.forename: Ruth
authors.initials: R
authors.lastname: Chia
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Cho
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Taymans
authors.forename: Mary K
authors.initials: MK
authors.lastname: Urban
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sancho
authors.forename: Marian
authors.initials: M
authors.lastname: Blanca Ramírez
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Berwick
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
mesh_terms: D000107:Acetylation; D000409:Alanine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D014404:Tubulin; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D008239:Lysine; D000409:Alanine
keywords: Cytoskeletal Dynamics; GTPase Mutation; Growth Cone; Lrrk2; Microtubules; Molecular Genetics; Parkinson Disease; RocCOR; Tubulin; Tubulin Acetylation