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Structural study of the RIPoptosome core reveals a helical assembly for kinase recruitment

Tae-ho Jang1, Chao Zheng, Jixi Li

  • 1School of Biotechnology and Graduate School of Biochemistry, Yeungnam University , Gyeongsan 712-749, South Korea.

Biochemistry
|August 15, 2014
PubMed

Insights

Receptor interaction protein kinase 1 (RIP1) forms a complex with FADD, crucial for cell death signaling. Structural analysis reveals a shared helical assembly mechanism with Fas signaling complexes, impacting apoptosis and necroptosis.

Area of Science:

  • Molecular and Cellular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Receptor interaction protein kinase 1 (RIP1) is a key regulator of cell fate, switching between apoptosis and necroptosis.
  • RIP1, FADD, and caspase-8 form the RIPoptosome, initiating apoptosis, while RIP1 and RIP3 form the necrosome, triggering necroptosis.
  • The assembly of these signaling complexes relies on specific protein-protein interactions, including those mediated by death domains (DDs) and death effector domains (DEDs).

Purpose of the Study:

  • To analyze the structural basis of RIPoptosome assembly by investigating the RIP1 DD/FADD DD complex.
  • To elucidate the commonalities in assembly mechanisms between the RIPoptosome and the Fas death-inducing signaling complex (DISC).

Main Methods:

  • Negative-stain electron microscopy was employed to determine the overall structure of the RIP1 DD/FADD DD complex.
  • Computational modeling was used in conjunction with experimental data to refine the structural analysis.
  • In vitro complex formation assays were performed to assess the stability and characteristics of the RIP1 DD/FADD DD interaction.

Main Results:

  • The RIP1 DD and FADD DD form a stable complex in vitro, mirroring the behavior of the Fas DD/FADD DD complex.
  • Structural analysis revealed a helical conformation for the RIP1 DD/FADD DD complex.
  • The assembly of both the RIPoptosome and Fas DISC appears to involve similar helical conformations and requires specific type I, II, and III interactions between death domains.

Conclusions:

  • The RIPoptosome and the Fas DISC share a common molecular assembly mechanism, driven by helical interactions of their death domains.
  • This structural similarity suggests conserved principles in the regulation of apoptosis and potentially other cell-death pathways mediated by RIP1 and Fas signaling.
  • Understanding these structural dynamics provides insights into the molecular switches governing cell fate.

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