Journal article
Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL
JM Murphy, IS Lucet, JM Hildebrand, MC Tanzer, SN Young, P Sharma, G Lessene, WS Alexander, JJ Babon, J Silke, PE Czabotar
Biochemical Journal | Published : 2014
DOI: 10.1042/BJ20131270
Abstract
The pseudokinase MLKL (mixed lineage kinase domain-like) was identified recently as an essential checkpoint in the programmed necrosis or 'necroptosis' cell death pathway. In the present study, we report the crystal structure of the human MLKL pseudokinase domain at 1.7 Å (1 Å=0.1 nm) resolution and probe its nucleotide-binding mechanism by performing structure-based mutagenesis. By comparing the structures and nucleotide-binding determinants of human and mouse MLKL orthologues, the present study provides insights into the evolution of nucleotidebinding mechanisms among pseudokinases and their mechanistic divergence from conventional catalytically active protein kinases. © 2014 Biochemical S..
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Funding Acknowledgements
This work was supported by the NHMRC (National Health and Medical Research Council) [grant numbers 637342, 1016647 and 1046984] and fellowships to J.M.H., W.S.A. and J.S.; Australian Research Council fellowships [FT100100100, FT110100169 and FT0992105] to J.M.M., J.J.B. and P.E.C.; a Victorian International Research Scholarship to M.C.T.; with additional support from the Victorian State Government Operational Infrastructure Support and NHMRC IRIISS (Independent Medical Research Institutes Infrastructure Support Scheme) [grant 361646]. J.S. is a member of the Scientific Advisory Board of TetraLogic Pharmaceuticals.