@article{8ea50f78b1074dceb857c0bc62ac33f6,
title = "Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues",
abstract = "The MLKL pseudokinase is the terminal effector in the necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL{\textquoteright}s conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, the plasma membrane to kill cells. The precise mechanisms underlying these processes are incompletely understood, and were proposed to differ between mouse and human cells. Here, we examine the divergence of activation mechanisms among nine vertebrate MLKL orthologues, revealing remarkable specificity of mouse and human RIPK3 for MLKL orthologues. Pig MLKL can restore necroptotic signaling in human cells; while horse and pig, but not rat, MLKL can reconstitute the mouse pathway. This selectivity can be rationalized from the distinct conformations observed in the crystal structures of horse and rat MLKL pseudokinase domains. These studies identify important differences in necroptotic signaling between species, and suggest that, more broadly, divergent regulatory mechanisms may exist among orthologous pseudoenzymes.",
author = "Davies, {Katherine A.} and Cheree Fitzgibbon and Young, {Samuel N.} and Garnish, {Sarah E.} and Wayland Yeung and Diane Coursier and Birkinshaw, {Richard W.} and Sandow, {Jarrod J.} and Lehmann, {Wil I.L.} and Liang, {Lung Yu} and Lucet, {Isabelle S.} and Chalmers, {James D.} and Patrick, {Wayne M.} and Natarajan Kannan and Petrie, {Emma J.} and Czabotar, {Peter E.} and Murphy, {James M.}",
note = "Funding Information: We thank staff at the Australian Synchrotron MX beamline for assistance with data collection. This research was undertaken in part using the MX2 crystallography beamline at the Australian Synchrotron, Victoria, Australia, and made use of the ACRF Detector. We gratefully acknowledge Clive Stone (Te Iwi o Ngātiwai) for enabling the tuatara MLKL sequence to be shared ahead of its publication. We acknowledge scholarship support for K.A.D. and S.E.G. (Australian Government Research Training Program Stipend Scholarships), L.-Y.L. (Melbourne Research Scholarship) and K.A.D. (AINSE PGRA scholarship). We are grateful to the National Health and Medical Research Council for fellowship (PEC, 1079700; JMM, 1105754, 1172929), grant (1057905; 1124735) and infrastructure (IRIISS 9000587) support; Australian Cancer Research Foundation; and the Victorian Government Operational Infrastructure Support scheme. Funding for N.K. from NIH (5R01GM114409) is acknowledged. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-16823-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}