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LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains

Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesi...

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Autores principales: Mórotz, Gábor M., Glennon, Elizabeth B., Gomez-Suaga, Patricia, Lau, Dawn H. W., Robinson, Eleanor D., Sedlák, Éva, Vagnoni, Alessio, Noble, Wendy, Miller, Christopher C. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505310/
https://www.ncbi.nlm.nih.gov/pubmed/31068217
http://dx.doi.org/10.1186/s40478-019-0715-5
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author Mórotz, Gábor M.
Glennon, Elizabeth B.
Gomez-Suaga, Patricia
Lau, Dawn H. W.
Robinson, Eleanor D.
Sedlák, Éva
Vagnoni, Alessio
Noble, Wendy
Miller, Christopher C. J.
author_facet Mórotz, Gábor M.
Glennon, Elizabeth B.
Gomez-Suaga, Patricia
Lau, Dawn H. W.
Robinson, Eleanor D.
Sedlák, Éva
Vagnoni, Alessio
Noble, Wendy
Miller, Christopher C. J.
author_sort Mórotz, Gábor M.
collection PubMed
description Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer’s disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer’s disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-019-0715-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-65053102019-05-10 LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains Mórotz, Gábor M. Glennon, Elizabeth B. Gomez-Suaga, Patricia Lau, Dawn H. W. Robinson, Eleanor D. Sedlák, Éva Vagnoni, Alessio Noble, Wendy Miller, Christopher C. J. Acta Neuropathol Commun Research Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. Thus, siRNA loss of KLC1 or mutation of the WD motif disrupts axonal transport of LMTK2. We also show that LMTK2 facilitates the formation of a complex containing KLC1 and p35 and that siRNA loss of LMTK2 disrupts axonal transport of both p35 and cdk5. Finally, we show that LMTK2 levels are reduced in Alzheimer’s disease brains. Damage to axonal transport and altered cdk5/p35 are pathogenic features of Alzheimer’s disease. Thus, LMTK2 binds to KLC1 to direct axonal transport of p35 and its loss may contribute to Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-019-0715-5) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-08 /pmc/articles/PMC6505310/ /pubmed/31068217 http://dx.doi.org/10.1186/s40478-019-0715-5 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Mórotz, Gábor M.
Glennon, Elizabeth B.
Gomez-Suaga, Patricia
Lau, Dawn H. W.
Robinson, Eleanor D.
Sedlák, Éva
Vagnoni, Alessio
Noble, Wendy
Miller, Christopher C. J.
LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains
title LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains
title_full LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains
title_fullStr LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains
title_full_unstemmed LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains
title_short LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer’s disease brains
title_sort lmtk2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and lmtk2 levels are reduced in alzheimer’s disease brains
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505310/
https://www.ncbi.nlm.nih.gov/pubmed/31068217
http://dx.doi.org/10.1186/s40478-019-0715-5
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