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Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3
Kinesin-1 transports numerous cellular cargoes along microtubules. The kinesin-1 light chain (KLC) mediates cargo binding and regulates kinesin-1 motility. To investigate the molecular basis for kinesin-1 recruitment and activation by cargoes, we solved the crystal structure of the KLC2 tetratricope...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224480/ https://www.ncbi.nlm.nih.gov/pubmed/30197037 http://dx.doi.org/10.1016/j.str.2018.07.011 |
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author | Cockburn, Joseph J.B. Hesketh, Sophie J. Mulhair, Peter Thomsen, Maren O'Connell, Mary J. Way, Michael |
author_facet | Cockburn, Joseph J.B. Hesketh, Sophie J. Mulhair, Peter Thomsen, Maren O'Connell, Mary J. Way, Michael |
author_sort | Cockburn, Joseph J.B. |
collection | PubMed |
description | Kinesin-1 transports numerous cellular cargoes along microtubules. The kinesin-1 light chain (KLC) mediates cargo binding and regulates kinesin-1 motility. To investigate the molecular basis for kinesin-1 recruitment and activation by cargoes, we solved the crystal structure of the KLC2 tetratricopeptide repeat (TPR) domain bound to the cargo JIP3. This, combined with biophysical and molecular evolutionary analyses, reveals a kinesin-1 cargo binding site, located on KLC TPR1, which is conserved in homologs from sponges to humans. In the complex, JIP3 crosslinks two KLC2 TPR domains via their TPR1s. We show that TPR1 forms a dimer interface that mimics JIP3 binding in all crystal structures of the unbound KLC TPR domain. We propose that cargo-induced dimerization of the KLC TPR domains via TPR1 is a general mechanism for activating kinesin-1. We relate this to activation by tryptophan-acidic cargoes, explaining how different cargoes activate kinesin-1 through related molecular mechanisms. |
format | Online Article Text |
id | pubmed-6224480 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62244802018-11-13 Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 Cockburn, Joseph J.B. Hesketh, Sophie J. Mulhair, Peter Thomsen, Maren O'Connell, Mary J. Way, Michael Structure Article Kinesin-1 transports numerous cellular cargoes along microtubules. The kinesin-1 light chain (KLC) mediates cargo binding and regulates kinesin-1 motility. To investigate the molecular basis for kinesin-1 recruitment and activation by cargoes, we solved the crystal structure of the KLC2 tetratricopeptide repeat (TPR) domain bound to the cargo JIP3. This, combined with biophysical and molecular evolutionary analyses, reveals a kinesin-1 cargo binding site, located on KLC TPR1, which is conserved in homologs from sponges to humans. In the complex, JIP3 crosslinks two KLC2 TPR domains via their TPR1s. We show that TPR1 forms a dimer interface that mimics JIP3 binding in all crystal structures of the unbound KLC TPR domain. We propose that cargo-induced dimerization of the KLC TPR domains via TPR1 is a general mechanism for activating kinesin-1. We relate this to activation by tryptophan-acidic cargoes, explaining how different cargoes activate kinesin-1 through related molecular mechanisms. Cell Press 2018-11-06 /pmc/articles/PMC6224480/ /pubmed/30197037 http://dx.doi.org/10.1016/j.str.2018.07.011 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cockburn, Joseph J.B. Hesketh, Sophie J. Mulhair, Peter Thomsen, Maren O'Connell, Mary J. Way, Michael Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 |
title | Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 |
title_full | Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 |
title_fullStr | Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 |
title_full_unstemmed | Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 |
title_short | Insights into Kinesin-1 Activation from the Crystal Structure of KLC2 Bound to JIP3 |
title_sort | insights into kinesin-1 activation from the crystal structure of klc2 bound to jip3 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224480/ https://www.ncbi.nlm.nih.gov/pubmed/30197037 http://dx.doi.org/10.1016/j.str.2018.07.011 |
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