Necroptosis is a form of inducible necrotic cell death that involves cell membrane rupture. MLKL is a major effector protein of necroptosis, but how it mediates this process is poorly understood. Quarato et al. used detailed structural analyses of MLKL to propose a model in which MLKL sequentially engages with the plasma membrane for necroptosis execution. MLKL first oligomerizes through interactions in a region known as the brace. This targets MLKL to the membrane, followed by interaction of the protein N-terminal helix bundle (NB) with membranous phosphatidylinositols. These interactions occur in two steps that engage distinct residues of the NB, with the second step inducing a conformational change in MLKL that displaces the brace from the NB and might serve as a 'plug release' mechanism, unleashing the membrane-permeabilizing activity of the NB.
References
Quarato, G. et al. Sequential engagement of distinct MLKL phosphatidylinositol-binding sites executes necroptosis. Mol. Cell http://dx.doi.org/10.1016/j.molcel.2016.01.011 (2016)
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Strzyz, P. Molecular insights into execution of necroptosis. Nat Rev Mol Cell Biol 17, 134 (2016). https://doi.org/10.1038/nrm.2016.17
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DOI: https://doi.org/10.1038/nrm.2016.17