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Journal of Cell BiologyVolume 216, Issue 4, 1 April 2017, Pages 943-960

Molecular mechanism of dynein recruitment to kinetochores by the Rod-Zw10-Zwilch complex and Spindly(Article)(Open Access)

  • Gama, J.B.,
  • Pereira, C.,
  • Simões, P.A.,
  • Celestino, R.,
  • Reis, R.M.,
  • Barbosa, D.J.,
  • Pires, H.R.,
  • Carvalho, C.,
  • Amorim, J.,
  • Carvalho, A.X.,
  • Cheerambathur, D.K.,
  • Gassmann, R.
  • View Correspondence (jump link)
  • aInstituto de Biologia Molecular e Celular, Universidade do Porto, Porto, 4200-135, Portugal
  • bInstituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal
  • cLudwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, United States
  • dDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, United States

Abstract

The molecular motor dynein concentrates at the kinetochore region of mitotic chromosomes in animals to accelerate spindle microtubule capture and to control spindle checkpoint signaling. In this study, we describe the molecular mechanism used by the Rod-Zw10-Zwilch complex and the adaptor Spindly to recruit dynein to kinetochores in Caenorhabditis elegans embryos and human cells. We show that Rod's N-terminal β-propeller and the associated Zwilch subunit bind Spindly's C-terminal domain, and we identify a specific Zwilch mutant that abrogates Spindly and dynein recruitment in vivo and Spindly binding to a Rod β-propeller-Zwilch complex in vitro. Spindly's N-terminal coiled-coil uses distinct motifs to bind dynein light intermediate chain and the pointed-end complex of dynactin. Mutations in these motifs inhibit assembly of a dynein-dynactin-Spindly complex, and a null mutant of the dynactin pointed-end subunit p27 prevents kinetochore recruitment of dynein-dynactin without affecting other mitotic functions of the motor. Conservation of Spindly-like motifs in adaptors involved in intracellular transport suggests a common mechanism for linking dynein to cargo. © 2017 Gama et al.

Indexed keywords

EMTREE drug terms:dynactindynein adenosine triphosphatasecarrier proteincell cycle proteindynactindynein adenosine triphosphatasemicrotubule associated proteinnonhistone protein
EMTREE medical terms:amino terminal sequenceArticlebinding siteCaenorhabditis eleganscarboxy terminal sequencecontrolled studyembryohumanhuman cellin vitro studyin vivo studyintracellular transportkinetochore microtubulemitosisnonhumannull allelepriority journalprotein motifprotein protein interactionsequence alignmentanimalchromosome segregationHeLa cell linekinetochoremetabolismmicrotubulephysiologyspindle apparatustumor cell line
MeSH:AnimalsCaenorhabditis elegansCarrier ProteinsCell Cycle ProteinsCell Line, TumorChromosomal Proteins, Non-HistoneChromosome SegregationDynactin ComplexDyneinsHeLa CellsHumansKinetochoresMicrotubule-Associated ProteinsMicrotubulesMitosisSpindle Apparatus

Chemicals and CAS Registry Numbers:

dynein adenosine triphosphatase; carrier protein, 80700-39-6;

Carrier Proteins; Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Dyneins; Microtubule-Associated Proteins

Funding details

Funding sponsor Funding number Acronym
European Molecular Biology Organization
See opportunities
Office of Extramural Research, National Institutes of HealthP40 OD010440
BPD_101898_2014,SFRH_BPD_95648_2013,IF/01015/2013/CP1157/CT0006
European Research Council338410

  • 1

    We wish to thank Andrea Musacchio for antibodies, Kevin Corbett for the 6?His::MBP expression vector, and Arshad Desai for generous support during the early stages of this project. This work was supported by a European Research Council Starting Grant (Dyneinome 338410) and a European Molecular Biology Organization Installation Grant to R. Gassmann. This work was also supported by funding from the Funda??o para a Ci?ncia e a Tecnologia to R. Gassmann (IF/01015/2013/CP1157/CT0006), C. Pereira (SFRH_BPD_95648_2013), and D.J. Barbosa (SFRH_ BPD_101898_2014). Some C. elegans strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440).

  • ISSN: 00219525
  • CODEN: JCLBA
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1083/jcb.201610108
  • PubMed ID: 28320824
  • Document Type: Article
  • Publisher: Rockefeller University Press

  Gassmann, R.; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal;
© Copyright 2017 Elsevier B.V., All rights reserved.

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