Autoinhibited kinesin-1 adopts a hierarchical folding pattern

Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mas...
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Autor*in:	Zhenyu Tan [verfasserIn] Yang Yue [verfasserIn] Felipe Leprevost [verfasserIn] Sarah Haynes [verfasserIn] Venkatesha Basrur [verfasserIn] Alexey I Nesvizhskii [verfasserIn] Kristen J Verhey [verfasserIn] Michael A Cianfrocco [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	motor protein kinesin AlphaFold crosslinking mass spectrometry integrative modeling

Übergeordnetes Werk:	In: eLife - eLife Sciences Publications Ltd, 2013, 12(2023)
Übergeordnetes Werk:	volume:12 ; year:2023

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.7554/eLife.86776

Katalog-ID:	DOAJ099595192

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allfields	10.7554/eLife.86776 doi (DE-627)DOAJ099595192 (DE-599)DOAJ51e8637d708c484a825bc54bda386b8e DE-627 ger DE-627 rakwb eng QH301-705.5 Zhenyu Tan verfasserin aut Autoinhibited kinesin-1 adopts a hierarchical folding pattern 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation. motor protein kinesin AlphaFold crosslinking mass spectrometry integrative modeling Medicine R Science Q Biology (General) Yang Yue verfasserin aut Felipe Leprevost verfasserin aut Sarah Haynes verfasserin aut Venkatesha Basrur verfasserin aut Alexey I Nesvizhskii verfasserin aut Kristen J Verhey verfasserin aut Michael A Cianfrocco verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.86776 kostenfrei https://doaj.org/article/51e8637d708c484a825bc54bda386b8e kostenfrei https://elifesciences.org/articles/86776 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
spelling	10.7554/eLife.86776 doi (DE-627)DOAJ099595192 (DE-599)DOAJ51e8637d708c484a825bc54bda386b8e DE-627 ger DE-627 rakwb eng QH301-705.5 Zhenyu Tan verfasserin aut Autoinhibited kinesin-1 adopts a hierarchical folding pattern 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation. motor protein kinesin AlphaFold crosslinking mass spectrometry integrative modeling Medicine R Science Q Biology (General) Yang Yue verfasserin aut Felipe Leprevost verfasserin aut Sarah Haynes verfasserin aut Venkatesha Basrur verfasserin aut Alexey I Nesvizhskii verfasserin aut Kristen J Verhey verfasserin aut Michael A Cianfrocco verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.86776 kostenfrei https://doaj.org/article/51e8637d708c484a825bc54bda386b8e kostenfrei https://elifesciences.org/articles/86776 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
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allfieldsSound	10.7554/eLife.86776 doi (DE-627)DOAJ099595192 (DE-599)DOAJ51e8637d708c484a825bc54bda386b8e DE-627 ger DE-627 rakwb eng QH301-705.5 Zhenyu Tan verfasserin aut Autoinhibited kinesin-1 adopts a hierarchical folding pattern 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation. motor protein kinesin AlphaFold crosslinking mass spectrometry integrative modeling Medicine R Science Q Biology (General) Yang Yue verfasserin aut Felipe Leprevost verfasserin aut Sarah Haynes verfasserin aut Venkatesha Basrur verfasserin aut Alexey I Nesvizhskii verfasserin aut Kristen J Verhey verfasserin aut Michael A Cianfrocco verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.86776 kostenfrei https://doaj.org/article/51e8637d708c484a825bc54bda386b8e kostenfrei https://elifesciences.org/articles/86776 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
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authorswithroles_txt_mv	Zhenyu Tan @@aut@@ Yang Yue @@aut@@ Felipe Leprevost @@aut@@ Sarah Haynes @@aut@@ Venkatesha Basrur @@aut@@ Alexey I Nesvizhskii @@aut@@ Kristen J Verhey @@aut@@ Michael A Cianfrocco @@aut@@
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callnumber-first	Q - Science
author	Zhenyu Tan
spellingShingle	Zhenyu Tan misc QH301-705.5 misc motor protein misc kinesin misc AlphaFold misc crosslinking mass spectrometry misc integrative modeling misc Medicine misc R misc Science misc Q misc Biology (General) Autoinhibited kinesin-1 adopts a hierarchical folding pattern
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topic_title	QH301-705.5 Autoinhibited kinesin-1 adopts a hierarchical folding pattern motor protein kinesin AlphaFold crosslinking mass spectrometry integrative modeling
topic	misc QH301-705.5 misc motor protein misc kinesin misc AlphaFold misc crosslinking mass spectrometry misc integrative modeling misc Medicine misc R misc Science misc Q misc Biology (General)
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title	Autoinhibited kinesin-1 adopts a hierarchical folding pattern
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title_sort	autoinhibited kinesin-1 adopts a hierarchical folding pattern
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title_auth	Autoinhibited kinesin-1 adopts a hierarchical folding pattern
abstract	Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation.
abstractGer	Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation.
abstract_unstemmed	Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation.
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title_short	Autoinhibited kinesin-1 adopts a hierarchical folding pattern
url	https://doi.org/10.7554/eLife.86776 https://doaj.org/article/51e8637d708c484a825bc54bda386b8e https://elifesciences.org/articles/86776 https://doaj.org/toc/2050-084X
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Autoinhibited kinesin-1 adopts a hierarchical folding pattern

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