Structural Insights into RIP3-Mediated Necroptotic Signaling

• DOI: 10.1016/j.celrep.2013.08.044
• Publication Date: 2013-10-03T15:15:18Z
• Authors: Tian Xie; Wei Peng; Chuangye Yan; Jianping Wu; Xinqi Gong; Yigong Shi
• Keywords: Models, Molecular; 0303 health sciences; QH301-705.5; Molecular Sequence Data; Protein Structure, Secondary; Mice; Necrosis; Xenopus laevis; 03 medical and health sciences; Receptor-Interacting Protein Serine-Threonine Kinases; Animals; Humans; Amino Acid Sequence; Biology (General); Phosphorylation; Protein Kinases; Signal Transduction

RIP3 is an essential upstream kinase in necroptosis. The pseudokinase MLKL functions as a substrate of to mediate downstream signaling. molecular mechanism by which recognizes and phosphorylates remains unknown. Here, we report the crystal structures mouse domain, kinase-like binary complex between two. Both adopt canonical fold. Free exists active conformation, whereas MLKL-bound stabilized AMP-PNP inactive conformation. formation RIP3-MLKL complex, involving their respective N- C-lobes, accompanied pronounced conformational changes αC helix activation loop corresponding structural elements MLKL. RIP3-mediated phosphorylation, though important for signaling, dispensable stable Our study serves framework mechanistic understanding necroptotic