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. 2021 Nov 22;12:6783. doi: 10.1038/s41467-021-27032-x

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — Human MLKL resides in a dormant state stably-complexed to RIPK3 in the cytoplasm via the bidentate interaction between MLKL and RIPK3 C-lobes. Following receipt of a necroptotic stimulus, RIPK3:MLKL complexes are recruited to the necrosome where RIPK3-mediated phosphorylation promotes MLKL structural interconversion, dissociation from the necrosome, and oligomerization⁴⁷. Mutational perturbation of the MLKL:RIPK3 interaction prevents their stable association and recruitment to the necrosome, identifying formation of stable MLKL:RIPK3 complexes as a crucial checkpoint in the necroptotic pathway. Recruitment to the necrosome allows engagement of chaperone- and Golgi/microtubule/actin-mediated pathways to facilitate MLKL translocation to the plasma membrane^32,56,57. Upon reaching a threshold level at the plasma membrane, MLKL can permeabilize membranes to cause cell death and damage-associated molecular pattern (DAMP) release. The skull and crossbones image (Mycomorphbox_Deadly.png; by Sven Manguard) was used under a Creative Commons Attribution-Share Alike 4.0 license.