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...
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| Veröffentlicht in: | Molecular cell 2012-09, Vol.47 (5), p.707-721 |
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| container_title | Molecular cell |
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| creator | 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. |
| 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.
► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker |
| doi_str_mv | 10.1016/j.molcel.2012.06.025 |
| format | Article |
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► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2012.06.025</identifier><identifier>PMID: 22857951</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ADP ; Animals ; cryo-electron microscopy ; electron microscopy ; Female ; humans ; kinesin ; Kinesin - metabolism ; Male ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins - deficiency ; Microtubule-Associated Proteins - metabolism ; microtubules ; Microtubules - metabolism ; molecular motor proteins ; motors ; mutation ; neurons ; Neurons - cytology ; Neurons - metabolism ; Neuropeptides - deficiency ; Neuropeptides - metabolism ; Protein-Serine-Threonine Kinases - deficiency ; Protein-Serine-Threonine Kinases - metabolism ; proteins ; synaptic vesicles</subject><ispartof>Molecular cell, 2012-09, Vol.47 (5), p.707-721</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><rights>2012 ELL & Excerpta Medica. 2012 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c586t-a0e0a502a2f804ddc54efdd439116e22265c65cd5ec0bceb5feeec1e9c395de93</citedby><cites>FETCH-LOGICAL-c586t-a0e0a502a2f804ddc54efdd439116e22265c65cd5ec0bceb5feeec1e9c395de93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1097276512005503$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22857951$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Judy S.</creatorcontrib><creatorcontrib>Schubert, Christian R.</creatorcontrib><creatorcontrib>Fu, Xiaoqin</creatorcontrib><creatorcontrib>Fourniol, Franck J.</creatorcontrib><creatorcontrib>Jaiswal, Jyoti K.</creatorcontrib><creatorcontrib>Houdusse, Anne</creatorcontrib><creatorcontrib>Stultz, Collin M.</creatorcontrib><creatorcontrib>Moores, Carolyn A.</creatorcontrib><creatorcontrib>Walsh, Christopher A.</creatorcontrib><title>Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><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.
► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker</description><subject>ADP</subject><subject>Animals</subject><subject>cryo-electron microscopy</subject><subject>electron microscopy</subject><subject>Female</subject><subject>humans</subject><subject>kinesin</subject><subject>Kinesin - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microtubule-Associated Proteins - deficiency</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>microtubules</subject><subject>Microtubules - metabolism</subject><subject>molecular motor proteins</subject><subject>motors</subject><subject>mutation</subject><subject>neurons</subject><subject>Neurons - cytology</subject><subject>Neurons - metabolism</subject><subject>Neuropeptides - deficiency</subject><subject>Neuropeptides - metabolism</subject><subject>Protein-Serine-Threonine Kinases - deficiency</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>proteins</subject><subject>synaptic vesicles</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUcFu1DAQjRCIlsIfIPCRS8LYsZ34gkQLBUQLiNKz5diTxausvdhJpf17XO1S4ALWSB5p3jy9ea-qnlJoKFD5ct1s4mRxahhQ1oBsgIl71TEF1dWcSn7_0LNOiqPqUc5rAMpFrx5WR4z1olOCHlfuMk5ol8kkcmqyz2SMiVxt0frRW_IVV2U0-xhIHMknXFIMZiIffcDsQ92SyzjHlMmwI2_iMhSmmGYfyLnZ-GlHvqQ4ow_5cfVgNFPGJ4f_pLo-f_vt7H198fndh7PXF7UVvZxrAwhGADNs7IE7ZwXH0TneKkolMsaksKWcQAuDxUGMiGgpKtsq4VC1J9WrPe92GTboLIY5mUlvk9-YtNPReP33JPjvehVvdCu44ooVghcHghR_LJhnvfG5eDyZgHHJmkF5QvYt_S-UAgelOtGKAuV7qE0x54TjnSIK-jZLvdb7LPVtlhqkLlmWtWd_XnO39Cu8Ani-B4wmarNKPuvrq8Igi8gWaCd_G4LF9RuPSWfrMVh0PqGdtYv-3xp-Akd8vYg</recordid><startdate>20120914</startdate><enddate>20120914</enddate><creator>Liu, Judy S.</creator><creator>Schubert, Christian R.</creator><creator>Fu, Xiaoqin</creator><creator>Fourniol, Franck J.</creator><creator>Jaiswal, Jyoti K.</creator><creator>Houdusse, Anne</creator><creator>Stultz, Collin M.</creator><creator>Moores, Carolyn A.</creator><creator>Walsh, Christopher A.</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20120914</creationdate><title>Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins</title><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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c586t-a0e0a502a2f804ddc54efdd439116e22265c65cd5ec0bceb5feeec1e9c395de93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ADP</topic><topic>Animals</topic><topic>cryo-electron microscopy</topic><topic>electron microscopy</topic><topic>Female</topic><topic>humans</topic><topic>kinesin</topic><topic>Kinesin - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microtubule-Associated Proteins - deficiency</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>microtubules</topic><topic>Microtubules - metabolism</topic><topic>molecular motor proteins</topic><topic>motors</topic><topic>mutation</topic><topic>neurons</topic><topic>Neurons - cytology</topic><topic>Neurons - metabolism</topic><topic>Neuropeptides - deficiency</topic><topic>Neuropeptides - metabolism</topic><topic>Protein-Serine-Threonine Kinases - deficiency</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>proteins</topic><topic>synaptic vesicles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Judy S.</creatorcontrib><creatorcontrib>Schubert, Christian R.</creatorcontrib><creatorcontrib>Fu, Xiaoqin</creatorcontrib><creatorcontrib>Fourniol, Franck J.</creatorcontrib><creatorcontrib>Jaiswal, Jyoti K.</creatorcontrib><creatorcontrib>Houdusse, Anne</creatorcontrib><creatorcontrib>Stultz, Collin M.</creatorcontrib><creatorcontrib>Moores, Carolyn A.</creatorcontrib><creatorcontrib>Walsh, Christopher A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Judy S.</au><au>Schubert, Christian R.</au><au>Fu, Xiaoqin</au><au>Fourniol, Franck J.</au><au>Jaiswal, Jyoti K.</au><au>Houdusse, Anne</au><au>Stultz, Collin M.</au><au>Moores, Carolyn A.</au><au>Walsh, Christopher A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2012-09-14</date><risdate>2012</risdate><volume>47</volume><issue>5</issue><spage>707</spage><epage>721</epage><pages>707-721</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>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.
► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22857951</pmid><doi>10.1016/j.molcel.2012.06.025</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | ADP Animals cryo-electron microscopy electron microscopy Female humans kinesin Kinesin - metabolism Male Mice Mice, Knockout Microtubule-Associated Proteins - deficiency Microtubule-Associated Proteins - metabolism microtubules Microtubules - metabolism molecular motor proteins motors mutation neurons Neurons - cytology Neurons - metabolism Neuropeptides - deficiency Neuropeptides - metabolism Protein-Serine-Threonine Kinases - deficiency Protein-Serine-Threonine Kinases - metabolism proteins synaptic vesicles |
| title | Molecular Basis for Specific Regulation of Neuronal Kinesin-3 Motors by Doublecortin Family Proteins |
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