ATP binds MLKL

Stable Identifier
R-HSA-9687625
Type
Reaction [binding]
Species
Homo sapiens
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Recombinant pseudokinase mixed lineage kinase domain-like (MLKL) exists in both monomeric form (∼30% of total) and tetrameric form (∼70% of total) in solution (Petrie EJ et al. 2018). Higher order oligomersof MLKL mediates necroptosis, an inflammatory form of programmed cell death executed through plasma membrane rupture (Wang H et al. 2014; Dondelinger Y et al. 2014; Tanzer MC et al. 2016; Petrie EJ et al. 2018; Samson AL et al. 2020). Biophysics, mass spectrometry (MS) and cellular assays revealed that the pseudokinase domain of human MLKL functions as a molecular switch in directing the transition of MLKL from a basal monomeric state to a pro-necroptotic tetramer (Petrie EJ et al. 2018). Despite lacking catalytic activity, the pseudokinase domain of MLKL has retained the ability to bind ATP (Murphy JM et al. 2013, 2014; Petrie EJ et al. 2018). The ATP binding has been shown to negatively regulate MLKL-mediated iposome permeabilization by destabilizing the MLKL tetramers and shifting the tetramer:monomer equilibrium toward the monomeric state (Petrie EJ et al. 2018). However, MLKL mutants with defective ATP-binding were still able to induce necroptosis when expressed in MLKL-/- HT-29 cells, suggesting that ATP-binding is most likely reflective of the ancestral function of the pseudokinase domain fold than regulatory in cells (Petrie EJ et al. 2018).

Literature References
PubMed ID Title Journal Year
29930286 Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis

Petrie, EJ, Sandow, JJ, Jacobsen, AV, Smith, BJ, Griffin, MDW, Lucet, IS, Dai, W, Young, SN, Tanzer, MC, Wardak, A, Liang, LY, Cowan, AD, Hildebrand, JM, Kersten, WJA, Lessene, G, Silke, J, Czabotar, PE, Webb, AI, Murphy, JM

Nat Commun 2018
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