Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain

The Biochemical Journal
Mark W RichardsRichard Bayliss

Abstract

Proteins of the echinoderm microtubule (MT)-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase MT network. EML1-4 consist of Trp-Asp 40 (WD40) repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4-ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding; however, this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4-ALK and EML1-ABL1 (Abelson 1) fusions in which variable portions of the EML component are present. Uniquely, EML4-ALK variant 3, which in...Continue Reading

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Citations

Jan 13, 2016·Cellular and Molecular Life Sciences : CMLS·Richard BaylissMark W Richards
May 4, 2017·Expert Opinion on Investigational Drugs·Niki KarachaliouRafael Rosell
Mar 2, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Martin Früh, Solange Peters
Jun 8, 2019·Journal of Anatomy·Stephan C CollinsFiona Francis
Aug 2, 2019·Cancers·Stephen P DucrayGerda Egger
Dec 3, 2016·Biochemical Society Transactions·Andrew M FryRichard Bayliss
Aug 17, 2019·Trends in Cell Biology·Satish BodakuntlaCarsten Janke
Mar 12, 2019·Current Medicinal Chemistry·Sitanshu S SinghSeetharama D Jois
Mar 18, 2020·Neurobiology of Disease·Denise K GrosenbaughHoward P Goodkin
Jun 13, 2020·Trends in Cancer·Yuwen LiGuoyu Meng
Jan 1, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·C G WooJ Choi

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