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dc.date.accessioned2018-06-04T15:35:20Z
dc.date.issued2014-04
dc.identifierhttp://publications.icr.ac.uk/13233/
dc.identifier.citationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (14), pp. 5195 - 5200
dc.identifier.issn0027-8424
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1698
dc.description.abstractProteins of the echinoderm microtubule-associated protein (EMAP)like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-angstrom crystal structure of the representative similar to 70-kDa core of EML1, revealing an intimately associated pair of beta-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two beta-propellers. The TAPE domain binds alpha/beta-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners.
dc.format.extent5195 - 5200
dc.languageeng
dc.language.isoeng
dc.subjectstructural biology stratified medicine CELL LUNG-CANCER MICROTUBULE-BINDING PROTEIN WD REPEAT PROTEIN FUSION ONCOGENE C-ELEGANS EMAP ALK INHIBITOR IDENTIFICATION RESISTANCE
dc.titleCrystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical beta-propeller domain
dc.typeJournal Article
rioxxterms.licenseref.startdate2014-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
pubs.issue14
pubs.notesISI Document Delivery No.: AE4VU Times Cited: 0 Cited Reference Count: 31 Richards, Mark W. Law, Edward W. P. Rennalls, La'Verne P. Busacca, Sara O'Regan, Laura Fry, Andrew M. Fennell, Dean A. Bayliss, Richard Royal Society Research Fellowship; Cancer Research UK Programme Grant [C24461/A13231]; Association for International Cancer Research; Wellcome Trust We thank Kiran Kulkarni and Ioannis Manolaridis (Institute of Cancer Research) for assistance with crystallography and Anne Straube (University of Warwick), Carolyn Moores (Birkbeck College), and Fiona Francis (University Pierre et Marie Curie, Paris) for helpful discussions. This work was supported by Royal Society Research Fellowship and Cancer Research UK Programme Grant C24461/A13231 (to R. B.) and by funding from the Association for International Cancer Research and the Wellcome Trust (A.M.F.). 0 NATL ACAD SCIENCES WASHINGTON P NATL ACAD SCI USA
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.volume111en_US
pubs.embargo.termsNot known
dc.contributor.icrauthorRennalls, La'Verneen


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