Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins
Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structur...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2013
|
| Online Access: | http://hdl.handle.net/1721.1/82159 https://orcid.org/0000-0002-3415-242X |
| _version_ | 1826189562689355776 |
|---|---|
| author | Liu, Judy S. Schubert, Christian R. Fu, Xiaoqin Fourniol, Franck J. Jaiswal, Jyoti K. Houdusse, Anne Stultz, Collin M. Moores, Carolyn A. Walsh, Christopher A. Schubert, Christian R. Stultz, Collin M. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Liu, Judy S. Schubert, Christian R. Fu, Xiaoqin Fourniol, Franck J. Jaiswal, Jyoti K. Houdusse, Anne Stultz, Collin M. Moores, Carolyn A. Walsh, Christopher A. Schubert, Christian R. Stultz, Collin M. |
| author_sort | Liu, Judy S. |
| collection | MIT |
| description | Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structurally conserved paralogue, doublecortin-like kinase 1 (Dclk1), show impaired Kif1a-mediated transport of Vamp2, a cargo of Kif1a, with decreased run length. Human disease-associated mutations in Dcx's linker sequence (e.g., W146C, K174E) alter Kif1a/Vamp2 transport by disrupting Dcx/Kif1a interactions without affecting Dcx MT binding. Dcx specifically enhances binding of the ADP-bound Kif1a motor domain to MTs. Cryo-electron microscopy and subnanometer-resolution image reconstruction reveal the kinesin-dependent conformational variability of MT-bound Dcx and suggest a model for MAP-motor crosstalk on MTs. Alteration of kinesin run length by MAPs represents a previously undiscovered mode of control of kinesin transport and provides a mechanism for regulation of MT-based transport by local signals. |
| first_indexed | 2024-09-23T08:17:16Z |
| format | Article |
| id | mit-1721.1/82159 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:17:16Z |
| publishDate | 2013 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/821592022-09-30T08:48:54Z Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins Liu, Judy S. Schubert, Christian R. Fu, Xiaoqin Fourniol, Franck J. Jaiswal, Jyoti K. Houdusse, Anne Stultz, Collin M. Moores, Carolyn A. Walsh, Christopher A. Schubert, Christian R. Stultz, Collin M. Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Research Laboratory of Electronics Schubert, Christian R. Stultz, Collin M. Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structurally conserved paralogue, doublecortin-like kinase 1 (Dclk1), show impaired Kif1a-mediated transport of Vamp2, a cargo of Kif1a, with decreased run length. Human disease-associated mutations in Dcx's linker sequence (e.g., W146C, K174E) alter Kif1a/Vamp2 transport by disrupting Dcx/Kif1a interactions without affecting Dcx MT binding. Dcx specifically enhances binding of the ADP-bound Kif1a motor domain to MTs. Cryo-electron microscopy and subnanometer-resolution image reconstruction reveal the kinesin-dependent conformational variability of MT-bound Dcx and suggest a model for MAP-motor crosstalk on MTs. Alteration of kinesin run length by MAPs represents a previously undiscovered mode of control of kinesin transport and provides a mechanism for regulation of MT-based transport by local signals. National Institutes of Health (U.S.) (Grant NIH-P30-HD-18655) National Institutes of Health (U.S.) (Grant 2T32NS007473-11) National Institutes of Health (U.S.) (Grant 2T32NS007484-11) National Institutes of Health (U.S.) (Grant 1F32D070549-01) National Science Foundation (U.S.) (CAREER Award) National Institutes of Health (U.S.) (Grant 5R21NS063185-02) 2013-11-18T16:06:49Z 2013-11-18T16:06:49Z 2012-07 2012-05 Article http://purl.org/eprint/type/JournalArticle 10972765 http://hdl.handle.net/1721.1/82159 Liu, Judy S., Christian R. Schubert, Xiaoqin Fu, Franck J. Fourniol, Jyoti K. Jaiswal, Anne Houdusse, Collin M. Stultz, Carolyn A. Moores, and Christopher A. Walsh. “Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins.” Molecular Cell 47, no. 5 (September 2012): 707-721. © 2012 Elsevier Inc. https://orcid.org/0000-0002-3415-242X en_US http://dx.doi.org/10.1016/j.molcel.2012.06.025 Molecular Cell Article is available under a Creative Commons license. http://creativecommons.org/ application/pdf Elsevier PMC |
| spellingShingle | Liu, Judy S. Schubert, Christian R. Fu, Xiaoqin Fourniol, Franck J. Jaiswal, Jyoti K. Houdusse, Anne Stultz, Collin M. Moores, Carolyn A. Walsh, Christopher A. Schubert, Christian R. Stultz, Collin M. Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
| title | Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
| title_full | Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
| title_fullStr | Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
| title_full_unstemmed | Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
| title_short | Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
| title_sort | molecular basis for specific regulation of neuronal kinesin 3 motors by doublecortin family proteins |
| url | http://hdl.handle.net/1721.1/82159 https://orcid.org/0000-0002-3415-242X |
| work_keys_str_mv | AT liujudys molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT schubertchristianr molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT fuxiaoqin molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT fourniolfranckj molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT jaiswaljyotik molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT houdusseanne molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT stultzcollinm molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT moorescarolyna molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT walshchristophera molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT schubertchristianr molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins AT stultzcollinm molecularbasisforspecificregulationofneuronalkinesin3motorsbydoublecortinfamilyproteins |