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Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization

  1. Author:
    Fujita, Hiroaki
    Tokunaga, Akira
    Shimizu, Satoshi
    Whiting, Amanda L
    Aguilar Alonso, Francisco
    Takagi, Kenji
    Walinda, Erik
    Sasaki, Yoshiteru
    Shimokawa, Taketo
    Mizushima, Tsunehiro
    Ohki, Izuru
    Ariyoshi, Mariko
    Tochio, Hidehito
    Bernal, Federico
    Shirakawa, Masahiro
    Iwai, Kazuhiro

  2. Author Address

    Department of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, Japan., Department of Molecular Engineering, Kyoto University School of Engineering, Kyoto 615-8510, Japan., Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan., Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Department of Picobiology, University of Hyogo School of Life Science, Hyogo 678-1297, Japan., Department of Biophysics, Kyoto University School of Science, Kyoto 606-8502, Japan., Department of Molecular and Cellular Physiology, Kyoto University School of Medicine, Kyoto 606-8501, Japan. Electronic address: kiwai@mcp.med.kyoto-u.ac.jp.,
    1. Year: 2018
    2. Date: Apr 24
  2. Journal: Cell Reports
    1. 23
    2. 4
    3. Pages: 1192-1204
  4. Type of Article: Article
  5. ISSN: 2211-1247
  1. Abstract:

    The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (UBA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2018.03.112
  3. PMID: 29694895
  4. View record in Web of Science®
  5. WOS: 000432453100024
  6. PII : S2211-1247(18)30488-1

Library Notes

  1. Fiscal Year: FY2017-2018
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