Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death

DOI Web Site 被引用文献11件
  • Joanne M. Hildebrand
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Maria C. Tanzer
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Isabelle S. Lucet
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Samuel N. Young
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Sukhdeep K. Spall
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Pooja Sharma
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Catia Pierotti
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Jean-Marc Garnier
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Renwick C. J. Dobson
    Biomolecular Interactions Centre, School of Biological Sciences, University of Canterbury, Christchurch, New Zealand;
  • Andrew I. Webb
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Anne Tripaydonis
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Jeffrey J. Babon
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Mark D. Mulcair
    Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; and
  • Martin J. Scanlon
    Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; and
  • Warren S. Alexander
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Andrew F. Wilks
    SynThesis MedChem, Parkville, VIC 3052, Australia
  • Peter E. Czabotar
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • Guillaume Lessene
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • James M. Murphy
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
  • John Silke
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;

抄録

<jats:title>Significance</jats:title> <jats:p>The four-helix bundle (4HB) domain of Mixed Lineage Kinase Domain-Like (MLKL) bears two clusters of residues that are required for cell death by necroptosis. Mutations within a cluster centered on the α4 helix of the 4HB domain of MLKL prevented its membrane translocation, oligomerization, and ability to induce necroptosis. This cluster is composed principally of acidic residues and therefore challenges the idea that the 4HB domain engages negatively charged phospholipid membranes via a conventional positively charged interaction surface. The importance of membrane translocation to MLKL-mediated death is supported by our identification of a small molecule that binds the MLKL pseudokinase domain and retards membrane translocation to inhibit necroptotic signaling.</jats:p>

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