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Kinetochore-Microtubule Attachment Throughout Mitosis Potentiated By Washington University School of Medicine Digital Commons@Becker Open Access Publications 2014 Kinetochore-microtubule attachment throughout mitosis potentiated by the elongated stalk of the kinetochore kinesin CENP-E Benjamin Vitre University of California - San Diego Nikita Gudimchuk University of Pennsylvania Ranier Borda University of California - San Diego Yumi Kim University of California - San Diego John E. Heuser Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Vitre, Benjamin; Gudimchuk, Nikita; Borda, Ranier; Kim, Yumi; Heuser, John E.; Cleveland, Don W.; and Grishchuk, Ekaterina L., ,"Kinetochore-microtubule attachment throughout mitosis potentiated by the elongated stalk of the kinetochore kinesin CENP-E." Molecular Biology of the Cell.25,15. 2272-2281. (2014). https://digitalcommons.wustl.edu/open_access_pubs/3207 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Benjamin Vitre, Nikita Gudimchuk, Ranier Borda, Yumi Kim, John E. Heuser, Don W. Cleveland, and Ekaterina L. Grishchuk This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/3207 M BoC | ARTICLE Kinetochore–microtubule attachment throughout mitosis potentiated by the elongated stalk of the kinetochore kinesin CENP-E Benjamin Vitrea,*, Nikita Gudimchukb,*,†, Ranier Bordaa, Yumi Kima,‡, John E. Heuserc,d, Don W. Clevelanda, and Ekaterina L. Grishchukb aLudwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093; bPhysiology Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cDepartment of Cell Biology, Washington University in Saint Louis, St Louis, MO 63110; dWPI Institute for Cell and Material Sciences, Kyoto University, Kyoto 606-8501, Japan ABSTRACT Centromere protein E (CENP-E) is a highly elongated kinesin that transports Monitoring Editor pole-proximal chromosomes during congression in prometaphase. During metaphase, it Kerry S. Bloom facilitates kinetochore–microtubule end-on attachment required to achieve and maintain University of North Carolina chromosome alignment. In vitro CENP-E can walk processively along microtubule tracks and Received: Jan 31, 2014 follow both growing and shrinking microtubule plus ends. Neither the CENP-E–dependent Revised: May 27, 2014 transport along microtubules nor its tip-tracking activity requires the unusually long coiled- Accepted: May 28, 2014 coil stalk of CENP-E. The biological role for the CENP-E stalk has now been identified through creation of “Bonsai” CENP-E with significantly shortened stalk but wild-type motor and tail domains. We demonstrate that Bonsai CENP-E fails to bind microtubules in vitro unless a cargo is contemporaneously bound via its C-terminal tail. In contrast, both full-length and truncated CENP-E that has no stalk and tail exhibit robust motility with and without cargo binding, highlighting the importance of CENP-E stalk for its activity. Correspondingly, kineto- chore attachment to microtubule ends is shown to be disrupted in cells whose CENP-E has a shortened stalk, thereby producing chromosome misalignment in metaphase and lagging chromosomes during anaphase. Together these findings establish an unexpected role of CENP-E elongated stalk in ensuring stability of kinetochore–microtubule attachments during chromosome congression and segregation. INTRODUCTION Accurate chromosome segregation in mitosis depends on the micro tubules. Kinetochores are complex multiprotein structures that dynamic interactions between the kinetochore and spindle localize at the centromeres of duplicated chromosomes during mi- tosis. The main function of the kinetochores is to connect chromo- This article was published online ahead of print in MBoC in Press (http://www somes to the mitotic spindle and mediate signaling the state of this .molbiolcell.org/cgi/doi/10.1091/mbc.E14-01-0698) on June 11, 2014. attachment to the cell cycle machinery (Cleveland et al., 2003). One *These authors contributed equally. kinetochore component, centromere protein E (CENP-E), is a plus Present addresses: †Center for Theoretical Problems of Physicochemical Pharma- cology, Russian Academy of Sciences, Moscow 119991, Russia; ‡Department of end–directed, microtubule-dependent motor from the kinesin-7 Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94704. family. Similar to other members of the kinesin superfamily, CENP-E Address correspondence to: Don W. Cleveland ([email protected]), Ekaterina is a homodimer, in which two motor domains are linked with two tail L. Grishchuk ([email protected]). domains via a dimerizing coiled coil. The stalk domain of CENP-E is Abbreviations used: aa, amino acid; ACA, anti–centromere antibodies; AMPPNP, adenylyl imidodiphosphate; ATP, adenosine triphosphate; BRB80, Brinkley re- highly elongated, spanning >200 nm (Kim et al., 2008), significantly assembly buffer; BS, Bonsai; DIC, differential interference contrast; FL, full length; longer than in most kinesins. This fibrillar kinesin accumulates before GFP, green fluorescent protein; MT, microtubule; NEB, nuclear envelope break- down; TIRF, total internal reflection fluorescence. mitosis (Brown et al., 1994), but soluble CENP-E molecules in the © 2014 Vitre, Gudimchuk, et al. This article is distributed by The American Society for cytoplasm of a mitotic cell are believed to be folded and inactive, as Cell Biology under license from the author(s). Two months after publication it is avail- the tail of CENP-E can bind the motor domains, inhibiting the micro- able to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported tubule-stimulated ATPase activity (Espeut et al., 2008). Previous Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of work also suggested that the initially autoinhibited CENP-E be- the Cell®” are registered trademarks of The American Society of Cell Biology. comes activated during mitosis via phosphorylation, which disrupts Supplemental Material can be found at: 2272 | B. Vitre, N. Gudimchuk, et al. http://www.molbiolcell.org/content/suppl/2014/06/02/mbc.E14-01-0698v1.DC1.html Molecular Biology of the Cell tail-mediated motor inhibition (Espeut et al., 2008). At mitosis onset, vitro, the truncated motor falls off microtubule ends and fails to CENP-E also becomes recruited to the outer layer of each kineto- track (Gudimchuk et al., 2013). Of interest, when purified tail and chore via its kinetochore-binding site located near its C-terminus motor domains are joined together using Quantum Dots, this pro- (Chan et al., 1998). A fully elongated extension of the active, kineto- duces conjugates that walk well along a microtubule wall and are chore-bound CENP-E may help to increase the span of the amino- able to recapitulate the processive association with the plus end of terminal motor domain from a bound kinetochore cargo, thereby dynamic microtubules characteristic of full-length CENP-E (Gudim- potentiating capture of spindle microtubules during prometaphase chuk et al., 2013). These experiments suggested that neither the (Kim et al., 2008, 2010; Gudimchuk et al., 2013). At the kinetochores tip-tracking activity nor the CENP-E–dependent transport along a of aligned chromosomes in metaphase, however, the CENP-E is not microtubule wall in vitro requires the elongated stalk of CENP-E, fully extended, and its conformation changes when the kinetochore raising a question about its contribution to CENP-E functions. is under tension (Wan et al., 2009). Through creation of “Bonsai” versions of CENP-E in which its stalk Results of the genetic depletion of CENP-E (Putkey et al., 2002; is significantly shortened but wild-type motor and tail domains are Weaver et al., 2003), its removal from kinetochores (McEwen et al., retained, we now identify the biological role for the CENP-E stalk. 2001), and inhibition of its motor activity (Gudimchuk et al., 2013) implicate CENP-E as an important kinetochore component that con- RESULTS tributes to high fidelity of chromosome segregation. CENP-E plays CENP-E coiled-coil stalk regulates motor function in vitro an essential role in transporting pole-proximal chromosomes to the Previous structural work visualizing purified CENP-E dimers with spindle equator during prometaphase, a process called chromo- electron microscopy reported that soluble CENP-E can adopt some congression (Yen et al., 1991; Schaar et al., 1997; Wood et al., many different conformations (Kim et al., 2008), consistent with a 1997). The initial congression of misaligned chromosomes takes highly flexible coiled-coil region. Direct examination of full-length place along already established kinetochore fibers and along the Xenopus CENP-E by electron microscopy using quick-freeze deep- microtubules directed to the spindle equator (Kapoor et al., 2006; etch and platinum replication (Heuser, 1989) identified a small pro- Cai et al., 2009). CENP-E–mediated chromosome motility requires portion of CENP-E molecules in a folded conformation
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