Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules
Lis1 is a key cofactor for the assembly of active cytoplasmic dynein complexes that transport cargo along microtubules. Lis1 binds to the AAA+ ring and stalk of dynein and slows dynein motility, but the underlying mechanism has remained unclear. Using single-molecule imaging and optical trapping ass...
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| Veröffentlicht in: | Nature chemical biology 2024-04, Vol.20 (4), p.521-529 |
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| creator | Kusakci, Emre Htet, Zaw Min Zhao, Yuanchang Gillies, John P. Reck-Peterson, Samara L. Yildiz, Ahmet |
| description | Lis1 is a key cofactor for the assembly of active cytoplasmic dynein complexes that transport cargo along microtubules. Lis1 binds to the AAA+ ring and stalk of dynein and slows dynein motility, but the underlying mechanism has remained unclear. Using single-molecule imaging and optical trapping assays, we investigated how Lis1 binding affects the motility and force generation of yeast dynein in vitro. We showed that Lis1 slows motility by binding to the AAA+ ring of dynein, not by serving as a roadblock or tethering dynein to microtubules. Lis1 binding also does not affect force generation, but it induces prolonged stalls and reduces the asymmetry in the force-induced detachment of dynein from microtubules. The mutagenesis of the Lis1-binding sites on the dynein stalk partially recovers this asymmetry but does not restore dynein velocity. These results suggest that Lis1–stalk interaction slows the detachment of dynein from microtubules by interfering with the stalk sliding mechanism.
Lis1 binding to the AAA+ ring of dynein increases the microtubule affinity and slows dynein motility. Lis1 binding to the stalk of dynein restricts the sliding of the coiled coils and slows detachment from microtubules under load. |
| doi_str_mv | 10.1038/s41589-023-01464-6 |
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Lis1 binding to the AAA+ ring of dynein increases the microtubule affinity and slows dynein motility. Lis1 binding to the stalk of dynein restricts the sliding of the coiled coils and slows detachment from microtubules under load.</description><identifier>ISSN: 1552-4450</identifier><identifier>ISSN: 1552-4469</identifier><identifier>EISSN: 1552-4469</identifier><identifier>DOI: 10.1038/s41589-023-01464-6</identifier><identifier>PMID: 37919547</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/136/334/2243 ; 631/57/2265 ; 631/80 ; 631/92/173 ; Asymmetry ; Binding sites ; Biochemical Engineering ; Biochemistry ; Bioorganic Chemistry ; Cell Biology ; Chemistry ; Chemistry and Materials Science ; Chemistry/Food Science ; Cytoplasmic Dyneins - metabolism ; Dynein ; Dyneins - chemistry ; Microtubule-Associated Proteins - metabolism ; Microtubules ; Microtubules - metabolism ; Motility ; Mutagenesis ; Optical trapping ; Saccharomyces cerevisiae - metabolism ; Sliding ; Tethering ; Yeasts</subject><ispartof>Nature chemical biology, 2024-04, Vol.20 (4), p.521-529</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2023. The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c426t-b1446e98b32bd643b6adb62afeca8e3cc34efa74c7c1f69cef1fcc1fd277e7583</cites><orcidid>0000-0003-4792-174X ; 0000-0003-1458-5321</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41589-023-01464-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41589-023-01464-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,778,782,883,27911,27912,41475,42544,51306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37919547$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kusakci, Emre</creatorcontrib><creatorcontrib>Htet, Zaw Min</creatorcontrib><creatorcontrib>Zhao, Yuanchang</creatorcontrib><creatorcontrib>Gillies, John P.</creatorcontrib><creatorcontrib>Reck-Peterson, Samara L.</creatorcontrib><creatorcontrib>Yildiz, Ahmet</creatorcontrib><title>Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules</title><title>Nature chemical biology</title><addtitle>Nat Chem Biol</addtitle><addtitle>Nat Chem Biol</addtitle><description>Lis1 is a key cofactor for the assembly of active cytoplasmic dynein complexes that transport cargo along microtubules. Lis1 binds to the AAA+ ring and stalk of dynein and slows dynein motility, but the underlying mechanism has remained unclear. Using single-molecule imaging and optical trapping assays, we investigated how Lis1 binding affects the motility and force generation of yeast dynein in vitro. We showed that Lis1 slows motility by binding to the AAA+ ring of dynein, not by serving as a roadblock or tethering dynein to microtubules. Lis1 binding also does not affect force generation, but it induces prolonged stalls and reduces the asymmetry in the force-induced detachment of dynein from microtubules. The mutagenesis of the Lis1-binding sites on the dynein stalk partially recovers this asymmetry but does not restore dynein velocity. These results suggest that Lis1–stalk interaction slows the detachment of dynein from microtubules by interfering with the stalk sliding mechanism.
Lis1 binding to the AAA+ ring of dynein increases the microtubule affinity and slows dynein motility. Lis1 binding to the stalk of dynein restricts the sliding of the coiled coils and slows detachment from microtubules under load.</description><subject>631/136/334/2243</subject><subject>631/57/2265</subject><subject>631/80</subject><subject>631/92/173</subject><subject>Asymmetry</subject><subject>Binding sites</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Bioorganic Chemistry</subject><subject>Cell Biology</subject><subject>Chemistry</subject><subject>Chemistry and Materials Science</subject><subject>Chemistry/Food Science</subject><subject>Cytoplasmic Dyneins - metabolism</subject><subject>Dynein</subject><subject>Dyneins - chemistry</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Microtubules</subject><subject>Microtubules - metabolism</subject><subject>Motility</subject><subject>Mutagenesis</subject><subject>Optical trapping</subject><subject>Saccharomyces cerevisiae - metabolism</subject><subject>Sliding</subject><subject>Tethering</subject><subject>Yeasts</subject><issn>1552-4450</issn><issn>1552-4469</issn><issn>1552-4469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UbtOxDAQtBCIg4MfoECRaGgCfsVxKoROvMRJNFBbjrOGnJL4sBPQ_T2GwPEoaNZr7ezs7A5CBwSfEMzkaeAkk0WKKUsx4YKnYgPtkCyjKeei2FznGZ6g3RAWGDMhiNxGE5YXpMh4voNu53UgSWjca0is8wbSuqsGA1VSQa_NUwtdnzibmFXvlo0ObW2SatVB3SXWuzaJf-_6oRwaCHtoy-omwP7nO0UPlxf3s-t0fnd1Mzufp4ZT0aclifKgkCWjZSU4K4WuSkG1BaMlMGMYB6tzbnJDrCgMWGJNTCua55Bnkk3R2ci7HMoWKhMlet2opa9b7VfK6Vr9rnT1k3p0L4oQIjhlIjIcfzJ49zxA6FVbBwNNoztwQ1BUSsEYJjFM0dEf6MINvov7KRYPynjBZBZRdETFa4Tgwa7VEKzezVKjWSqapT7MUu8qDn_usW75cicC2AgIsdQ9gv-e_Q_tG_NnogE</recordid><startdate>20240401</startdate><enddate>20240401</enddate><creator>Kusakci, Emre</creator><creator>Htet, Zaw Min</creator><creator>Zhao, Yuanchang</creator><creator>Gillies, John P.</creator><creator>Reck-Peterson, Samara L.</creator><creator>Yildiz, Ahmet</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4792-174X</orcidid><orcidid>https://orcid.org/0000-0003-1458-5321</orcidid></search><sort><creationdate>20240401</creationdate><title>Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules</title><author>Kusakci, Emre ; 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Lis1 binds to the AAA+ ring and stalk of dynein and slows dynein motility, but the underlying mechanism has remained unclear. Using single-molecule imaging and optical trapping assays, we investigated how Lis1 binding affects the motility and force generation of yeast dynein in vitro. We showed that Lis1 slows motility by binding to the AAA+ ring of dynein, not by serving as a roadblock or tethering dynein to microtubules. Lis1 binding also does not affect force generation, but it induces prolonged stalls and reduces the asymmetry in the force-induced detachment of dynein from microtubules. The mutagenesis of the Lis1-binding sites on the dynein stalk partially recovers this asymmetry but does not restore dynein velocity. These results suggest that Lis1–stalk interaction slows the detachment of dynein from microtubules by interfering with the stalk sliding mechanism.
Lis1 binding to the AAA+ ring of dynein increases the microtubule affinity and slows dynein motility. Lis1 binding to the stalk of dynein restricts the sliding of the coiled coils and slows detachment from microtubules under load.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>37919547</pmid><doi>10.1038/s41589-023-01464-6</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-4792-174X</orcidid><orcidid>https://orcid.org/0000-0003-1458-5321</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/136/334/2243 631/57/2265 631/80 631/92/173 Asymmetry Binding sites Biochemical Engineering Biochemistry Bioorganic Chemistry Cell Biology Chemistry Chemistry and Materials Science Chemistry/Food Science Cytoplasmic Dyneins - metabolism Dynein Dyneins - chemistry Microtubule-Associated Proteins - metabolism Microtubules Microtubules - metabolism Motility Mutagenesis Optical trapping Saccharomyces cerevisiae - metabolism Sliding Tethering Yeasts |
| title | Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules |
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