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      Structural insights into RIP3-mediated necroptotic signaling.

      1 , , , , ,
      Cell reports

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          Abstract

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

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          Author and article information

          Journal
          Cell Rep
          Cell reports
          2211-1247
          Oct 17 2013
          : 5
          : 1
          Affiliations
          [1 ] Ministry of Education Protein Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
          Article
          S2211-1247(13)00504-4
          10.1016/j.celrep.2013.08.044
          24095729
          a0801241-5386-412e-ad34-af8a9aa8eda9
          Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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