The brace helices of MLKL mediate interdomain communication and oligomerisation to regulate cell death by necroptosis View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-09

AUTHORS

Katherine A. Davies, Maria C. Tanzer, Michael D. W. Griffin, Yee Foong Mok, Samuel N. Young, Rui Qin, Emma J. Petrie, Peter E. Czabotar, John Silke, James M. Murphy

ABSTRACT

The programmed cell death pathway, necroptosis, relies on the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), for cellular execution downstream of death receptor or Toll-like receptor ligation. Receptor-interacting protein kinase-3 (RIPK3)-mediated phosphorylation of MLKL's pseudokinase domain leads to MLKL switching from an inert to activated state, where exposure of the N-terminal four-helix bundle (4HB) 'executioner' domain leads to cell death. The precise molecular details of MLKL activation, including the stoichiometry of oligomer assemblies, mechanisms of membrane translocation and permeabilisation, remain a matter of debate. Here, we dissect the function of the two 'brace' helices that connect the 4HB to the pseudokinase domain of MLKL. In addition to establishing that the integrity of the second brace helix is crucial for the assembly of mouse MLKL homotrimers and cell death, we implicate the brace helices as a device to communicate pseudokinase domain phosphorylation event(s) to the N-terminal executioner 4HB domain. Using mouse:human MLKL chimeras, we defined the first brace helix and adjacent loop as key elements of the molecular switch mechanism that relay pseudokinase domain phosphorylation to the activation of the 4HB domain killing activity. In addition, our chimera data revealed the importance of the pseudokinase domain in conferring host specificity on MLKL killing function, where fusion of the mouse pseudokinase domain converted the human 4HB + brace from inactive to a constitutive killer of mouse fibroblasts. These findings illustrate that the brace helices play an active role in MLKL regulation, rather than simply acting as a tether between the 4HB and pseudokinase domains. More... »

PAGES

1567-1580

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41418-018-0061-3

    DOI

    http://dx.doi.org/10.1038/s41418-018-0061-3

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1101033647

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29445128


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