Kinesin processivity is gated by phosphate release
Kinesin-1 is a dimeric motor protein, central to intracellular transport, that steps hand-over-hand toward the microtubule (MT) plus-end, hydrolyzing one ATP molecule per step. Its remarkable processivity is critical for ferrying cargo within the cell: over 100 successive steps are taken, on average...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2014-09, Vol.111 (39), p.14136-14140 |
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creator | Milic, Bojan Andreasson, Johan O. L. Hancock, William O. Block, Steven M. |
description | Kinesin-1 is a dimeric motor protein, central to intracellular transport, that steps hand-over-hand toward the microtubule (MT) plus-end, hydrolyzing one ATP molecule per step. Its remarkable processivity is critical for ferrying cargo within the cell: over 100 successive steps are taken, on average, before dissociation from the MT. Despite considerable work, it is not understood which features coordinate, or “gate,” the mechanochemical cycles of the two motor heads. Here, we show that kinesin dissociation occurs subsequent to, or concomitant with, phosphate (P ᵢ) release following ATP hydrolysis. In optical trapping experiments, we found that increasing the steady-state population of the posthydrolysis ADP·P ᵢ state (by adding free P ᵢ) nearly doubled the kinesin run length, whereas reducing either the ATP binding rate or hydrolysis rate had no effect. The data suggest that, during processive movement, tethered-head binding occurs subsequent to hydrolysis, rather than immediately after ATP binding, as commonly suggested. The structural change driving motility, thought to be neck linker docking, is therefore completed only upon hydrolysis, and not ATP binding. Our results offer additional insights into gating mechanisms and suggest revisions to prevailing models of the kinesin reaction cycle.
Significance Kinesin-1 is a motor protein central to intracellular transport. Prevailing models of the kinesin mechanochemical cycle—which invoke docking of the neck linker domain upon ATP binding—fail to explain the remarkable processivity of kinesin, which represents a competition between dissociation from the microtubule and continuation of the stepping cycle. We show that kinesin dissociation, which characterizes the end of a processive run, is gated by phosphate release following ATP hydrolysis. The structural change driving kinesin motility, likely neck linker docking, is therefore completed only upon hydrolysis. Our results offer insights into gating mechanisms and necessitate revisions to existing models of the kinesin cycle. |
doi_str_mv | 10.1073/pnas.1410943111 |
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Significance Kinesin-1 is a motor protein central to intracellular transport. Prevailing models of the kinesin mechanochemical cycle—which invoke docking of the neck linker domain upon ATP binding—fail to explain the remarkable processivity of kinesin, which represents a competition between dissociation from the microtubule and continuation of the stepping cycle. We show that kinesin dissociation, which characterizes the end of a processive run, is gated by phosphate release following ATP hydrolysis. The structural change driving kinesin motility, likely neck linker docking, is therefore completed only upon hydrolysis. Our results offer insights into gating mechanisms and necessitate revisions to existing models of the kinesin cycle.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1410943111</identifier><identifier>PMID: 25197045</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenosine triphosphatase ; adenosine triphosphate ; Adenosine Triphosphate - metabolism ; Animals ; Binding sites ; Biochemistry ; Biological Sciences ; Biophysical Phenomena ; Chemical reactions ; Dimers ; dissociation ; Drosophila Proteins - chemistry ; Drosophila Proteins - genetics ; Drosophila Proteins - metabolism ; Freight ; Hydrolysis ; kinesin ; Kinesin - chemistry ; Kinesin - genetics ; Kinesin - metabolism ; Kinetics ; Microtubules ; Models, Biological ; molecular motor proteins ; Molecular Motor Proteins - chemistry ; Molecular Motor Proteins - genetics ; Molecular Motor Proteins - metabolism ; Molecules ; Motors ; Nucleotides ; Optical Tweezers ; Phosphates ; Phosphates - metabolism ; Protein Structure, Quaternary ; Proteins ; Recombinant Fusion Proteins - chemistry ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-09, Vol.111 (39), p.14136-14140</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Sep 30, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-39d78e85c823cd2e8f4d0565e9cf5921819d53f3be1330d9dc81d950cb432713</citedby><cites>FETCH-LOGICAL-c591t-39d78e85c823cd2e8f4d0565e9cf5921819d53f3be1330d9dc81d950cb432713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/39.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/43055048$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/43055048$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25197045$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Milic, Bojan</creatorcontrib><creatorcontrib>Andreasson, Johan O. L.</creatorcontrib><creatorcontrib>Hancock, William O.</creatorcontrib><creatorcontrib>Block, Steven M.</creatorcontrib><title>Kinesin processivity is gated by phosphate release</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Kinesin-1 is a dimeric motor protein, central to intracellular transport, that steps hand-over-hand toward the microtubule (MT) plus-end, hydrolyzing one ATP molecule per step. Its remarkable processivity is critical for ferrying cargo within the cell: over 100 successive steps are taken, on average, before dissociation from the MT. Despite considerable work, it is not understood which features coordinate, or “gate,” the mechanochemical cycles of the two motor heads. Here, we show that kinesin dissociation occurs subsequent to, or concomitant with, phosphate (P ᵢ) release following ATP hydrolysis. In optical trapping experiments, we found that increasing the steady-state population of the posthydrolysis ADP·P ᵢ state (by adding free P ᵢ) nearly doubled the kinesin run length, whereas reducing either the ATP binding rate or hydrolysis rate had no effect. The data suggest that, during processive movement, tethered-head binding occurs subsequent to hydrolysis, rather than immediately after ATP binding, as commonly suggested. The structural change driving motility, thought to be neck linker docking, is therefore completed only upon hydrolysis, and not ATP binding. Our results offer additional insights into gating mechanisms and suggest revisions to prevailing models of the kinesin reaction cycle.
Significance Kinesin-1 is a motor protein central to intracellular transport. Prevailing models of the kinesin mechanochemical cycle—which invoke docking of the neck linker domain upon ATP binding—fail to explain the remarkable processivity of kinesin, which represents a competition between dissociation from the microtubule and continuation of the stepping cycle. We show that kinesin dissociation, which characterizes the end of a processive run, is gated by phosphate release following ATP hydrolysis. The structural change driving kinesin motility, likely neck linker docking, is therefore completed only upon hydrolysis. Our results offer insights into gating mechanisms and necessitate revisions to existing models of the kinesin cycle.</description><subject>Adenosine triphosphatase</subject><subject>adenosine triphosphate</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Biological Sciences</subject><subject>Biophysical Phenomena</subject><subject>Chemical reactions</subject><subject>Dimers</subject><subject>dissociation</subject><subject>Drosophila Proteins - chemistry</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Freight</subject><subject>Hydrolysis</subject><subject>kinesin</subject><subject>Kinesin - chemistry</subject><subject>Kinesin - genetics</subject><subject>Kinesin - metabolism</subject><subject>Kinetics</subject><subject>Microtubules</subject><subject>Models, Biological</subject><subject>molecular motor proteins</subject><subject>Molecular Motor Proteins - chemistry</subject><subject>Molecular Motor Proteins - genetics</subject><subject>Molecular Motor Proteins - metabolism</subject><subject>Molecules</subject><subject>Motors</subject><subject>Nucleotides</subject><subject>Optical Tweezers</subject><subject>Phosphates</subject><subject>Phosphates - metabolism</subject><subject>Protein Structure, Quaternary</subject><subject>Proteins</subject><subject>Recombinant Fusion Proteins - chemistry</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtvEzEUhS0EoqGwZgWMxIbNtPf6MWNvkFDFS63EgrK2HNuTOJqMB3tSKf8ejxIC7aYr27rfPTo-h5DXCBcILbscB5MvkCMozhDxCVmUK9YNV_CULABoW0tO-Rl5kfMGAJSQ8JycUYGqBS4WhF6HwecwVGOK1ucc7sK0r0KuVmbyrlruq3Ed87guryr53pvsX5Jnnemzf3U8z8ntl8-3V9_qmx9fv199uqmtUDjVTLlWeimspMw66mXHHYhGeGU7oShKVE6wji09MgZOOSvRKQF2yRltkZ2TjwfZcbfcemf9MCXT6zGFrUl7HU3Q9ydDWOtVvNMcFbZiFvhwFEjx987nSW9Dtr7vzeDjLmuUwJAp1vLHUdG0UDJTTUHfP0A3cZeGEoTGpmQPDcIseHmgbIo5J9-dfCPouTk9N6f_NVc23v7_3RP_t6oCVEdg3jzJIWqmZiE2e3tzQDZ5iunEcAZCAJdl_u4w70zUZpVC1r9-Uii-oQRBEdgfsMywEQ</recordid><startdate>20140930</startdate><enddate>20140930</enddate><creator>Milic, Bojan</creator><creator>Andreasson, Johan O. 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L.</au><au>Hancock, William O.</au><au>Block, Steven M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kinesin processivity is gated by phosphate release</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2014-09-30</date><risdate>2014</risdate><volume>111</volume><issue>39</issue><spage>14136</spage><epage>14140</epage><pages>14136-14140</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Kinesin-1 is a dimeric motor protein, central to intracellular transport, that steps hand-over-hand toward the microtubule (MT) plus-end, hydrolyzing one ATP molecule per step. Its remarkable processivity is critical for ferrying cargo within the cell: over 100 successive steps are taken, on average, before dissociation from the MT. Despite considerable work, it is not understood which features coordinate, or “gate,” the mechanochemical cycles of the two motor heads. Here, we show that kinesin dissociation occurs subsequent to, or concomitant with, phosphate (P ᵢ) release following ATP hydrolysis. In optical trapping experiments, we found that increasing the steady-state population of the posthydrolysis ADP·P ᵢ state (by adding free P ᵢ) nearly doubled the kinesin run length, whereas reducing either the ATP binding rate or hydrolysis rate had no effect. The data suggest that, during processive movement, tethered-head binding occurs subsequent to hydrolysis, rather than immediately after ATP binding, as commonly suggested. The structural change driving motility, thought to be neck linker docking, is therefore completed only upon hydrolysis, and not ATP binding. Our results offer additional insights into gating mechanisms and suggest revisions to prevailing models of the kinesin reaction cycle.
Significance Kinesin-1 is a motor protein central to intracellular transport. Prevailing models of the kinesin mechanochemical cycle—which invoke docking of the neck linker domain upon ATP binding—fail to explain the remarkable processivity of kinesin, which represents a competition between dissociation from the microtubule and continuation of the stepping cycle. We show that kinesin dissociation, which characterizes the end of a processive run, is gated by phosphate release following ATP hydrolysis. The structural change driving kinesin motility, likely neck linker docking, is therefore completed only upon hydrolysis. Our results offer insights into gating mechanisms and necessitate revisions to existing models of the kinesin cycle.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>25197045</pmid><doi>10.1073/pnas.1410943111</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adenosine triphosphatase adenosine triphosphate Adenosine Triphosphate - metabolism Animals Binding sites Biochemistry Biological Sciences Biophysical Phenomena Chemical reactions Dimers dissociation Drosophila Proteins - chemistry Drosophila Proteins - genetics Drosophila Proteins - metabolism Freight Hydrolysis kinesin Kinesin - chemistry Kinesin - genetics Kinesin - metabolism Kinetics Microtubules Models, Biological molecular motor proteins Molecular Motor Proteins - chemistry Molecular Motor Proteins - genetics Molecular Motor Proteins - metabolism Molecules Motors Nucleotides Optical Tweezers Phosphates Phosphates - metabolism Protein Structure, Quaternary Proteins Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism |
title | Kinesin processivity is gated by phosphate release |
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