Structural principles of tumor necrosis factor superfamily signaling

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Sci. Signal.  02 Jan 2018:
Vol. 11, Issue 511, eaao4910
DOI: 10.1126/scisignal.aao4910


  • Fig. 1 Representative structures of TNFSF ligand-receptor complexes and their downstream signaling partners.

    (A) The tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL)–death receptor 5 (DR5) complex [Protein Data Bank (PDB) ID: 1DU3] represents the structure of a death domain (DD)–interacting TNF superfamily (TNFSF) receptor and its ligand shown in cartoon representation as side (left) and top view (right). The TRAIL ligand trimer is shown in magenta surrounded by three monomers of the DR5 receptor shown in blue. The zinc ion of TRAIL is shown as a gray sphere. (B) Below the cell membrane, the intracellular portion of DR5 contains a DD that can exist in a closed (orange) or open (blue) conformation shown in a schematic representation based on the structure of the FasDD (73). Two helices, helices 5 and 6, are highlighted. Upon activation, the conformational change of helix 6 results in the formation of a long helix that enables DD dimerization and the binding of Fas-associated death domain (FADD) (shown in green). The red circles show the trimerization interface. (C) The TNF–TNF receptor 2 (TNFR2) complex (PDB ID: 3ALQ) illustrates a TNFR-associated factor (TRAF)–interacting TNFR in complex with its ligand. A trimeric TNF ligand (magenta) is bound on the outside by three TNFR2 receptor monomers (blue). In one of the TNFR2 receptor monomers on the far right, the four cysteine-rich domains (CRD1 to CRD4) are labeled and the disulfide bonds are illustrated as yellow spheres. (D) The intracellular portion of TNFR2 (blue line) interacts with TRAF2 shown in chartreuse. TRAF2 consists of three major parts: the TRAF2 C-terminal (TRAF2-C) domain, a long coiled coil (CC) domain, and the TRAF2 N-terminal domain. The structural model of the TRAF2-C–CC complex was created by merging the structures of the TRAF2-C–TNFR2 peptide complex (PDB ID: 1CA9) and the TRAF2 CC domain (PDB ID: 3M06). The black arrow indicates the cellular inhibitor of apoptosis protein 1 or 2 (cIAP1/2)–binding site. The TRAF2 N-terminal domain is made up of four zinc finger domains (ZF1 to ZF4) and a really interesting new gene (RING) domain shown in a schematic representation. Upon activation, TRAF2 trimerizes and activates downstream signaling events, resulting in canonical or noncanonical nuclear factor κB (NF-κB) activation. The program PyMOL was used to create the molecular representations (96).

  • Fig. 2 Parallel and antiparallel dimer models.

    (A) Side view of the parallel TNFR dimer model based on the structure of soluble TNFR1 (PDB ID: 1NCF). In the parallel dimer, the receptor monomers are arranged in a back-to-back fashion, exposing the ligand-binding site. The receptors are shown both in cartoon representation (blue) and as surface model (white). The N and C terminus of each monomer is labeled. The parallel dimers can cluster on the cell surface, creating a dense network (lower, top view). The receptors are represented as surface filling models. The dashed lines indicate the dimer axis. (B) The antiparallel dimers are formed between the N-terminal, CRD1, and CRD2 portions of the receptor burying the ligand-binding site. The lower panel shows in top view how antiparallel dimers can arrange on the cell surface forming a large hexagonal network. The red rectangle represents a single antiparallel dimer. The vertices where three receptors come together indicate the ligand-binding site. Dotted lines illustrate the dimer axis.

  • Fig. 3 Hexagonal models of extracellular and intracellular signaling networks.

    (A) Structural representation of the hexagonal network model of a TNFSF ligand–DR–agonist antibody (AgAb) complex (TNFSF-DR–AgAb) based on the TRAIL–DR5–AMG 655 structure (top left; PDB ID: 4N90) (70). In top view, the TNFSF ligand trimers are shown in magenta, surrounded by three receptors shown in blue. Each ligand-receptor complex is cross-linked by an agonist antibody F(ab′)2 fragment (green) that stabilizes the hexagonal network. (B) Hexagonal model of the downstream signaling partner of the DR complex shown in (A). The TNFRDD-FADD complex shown in Fig. 1B can cluster to form a hexagonal network (73). (C) Receptor resting state model based on the hexagonal antiparallel dimer network shown in Fig. 2B. (D) TRAFs represented in Fig. 1D can form hexagonal networks via the dimerization of the TRAF N-terminal RING domains. Coloring is the same as in Fig. 1D. All four models in (A) to (D) are built on the same hexagonal lattice indicating a common arrangement for TNFSF DRs, TRAF-associated TNFRs, and their downstream signaling partners.

  • Fig. 4 TNFSF resting state and activation model.

    TNFSF receptor monomers (shown in blue) form antiparallel dimers that exclude the ligand, thus representing the resting state. The combination of the trimer and dimer symmetries results in the formation of a hexagonal network represented in top view on the right side. The hexagons can be repeated to form an infinite network. The nonsignaling state of the receptor can be stabilized by antagonist antibodies (shown in yellow) that lock in the antiparallel dimers, and thus block ligand binding and signaling. For dominant inhibition, the full antibody or an F(ab′)2 fragment is required. In the absence of a blocking antagonist antibody, TNFSF ligand binding activates the receptors to form signaling complexes that retain the hexagonal symmetry. The TNFSF ligand likely comes into contact with the receptor at the exposed stem region and initiates the conformational change required for ligand binding, as illustrated by the red arrows. The resulting signaling network can be stabilized by cross-linking agonist antibodies shown in green. The protein molecules are shown in surface representation using the same coloring as before.



  • Table 1 TNFRSF receptors, their ligands, and their intracellular binding partners.

    TNFRSF members can be classified into three groups based on their downstream interaction partners. Some receptors can be activated by more than one ligand. EDARADD, EDAR-associated DD; NADE, neurotrophin-associated cell death executor; NGF, nerve growth factor; NGFR, NGF receptor; n/a, not applicable.

    TNFRSF receptor (TNFRSF#, other names)Intracellular binding partnerTNFSF ligand (TNFSF#, other names)
    Death receptors
      TNFR1 (1a, CD120a)TRADD, FADD, RIPTNF (2, TNF-α), LTα (1, TNF-β), LTβ (3)
      Fas (6, CD95)FADDFasL (6, CD178)
      TRAILR1 (10A, DR4, CD261)FADD, TRADD, RIPTRAIL/Apo2L (10, CD253)
      TRAILR2 (10B, DR5, CD262)FADD, TRADD, RIPTRAIL/Apo2L (10, CD253)
      NGFR (16, p75NTR, CD271)NADENGF (not a TNFSF member)
      DR3 (25 or 12, TRAMP)TRADD, FADDTL1A (15, VEGI), TWEAK (12)
      DR6 (21, CD358)TRADD, RIPN-APP (not a TNFSF member)
    Receptors with TRAF-interacting motif (82)
      TNFR2 (1b, CD120b)TRAF1–3TNF (2, TNF-α), LTα (1, TNF-β), LTβ (3)
      LTβR (3)TRAF2, TRAF3, TRAF5LTβ (3), LTαβ2
      OX40 (4, CD134)TRAF1–3, TRAF5, TRAF6OX40L (4, CD252)
      CD40 (5)TRAF1–3, TRAF5, TRAF6CD40L (5, CD154)
      CD27 (7)TRAF2, TRAF3, TRAF5CD27L (7, CD70)
      CD30 (8)TRAF1–3, TRAF5CD30L (8, CD153)
      4-1BB (9, CD137)TRAF1–34-1BBL (9, CD137L)
      RANK (11A, CD265)TRAF1–3, TRAF5, TRAF6RANKL (11, TRANCE, CD254)
      Fn14 (12A, TWEAKR; CD266)TRAF2, TRAF6TWEAK (12)
      TACI (13B, CD267)TRAF2–3, TRAF5, TRAF6APRIL (13, CD256)
      BAFFR (13C, BR3, CD268)TRAF2, TRAF3, TRAF6BAFF (13B/20, BLys, THANK, CD257)
      HVEM (14, CD270)TRAF1–3, TRAF5LIGHT (14, CD258), LTα (1, TNF-β)
      BCMA (17, CD269)TRAF1–3, TRAF5, TRAF6APRIL (13, CD256), BAFF (13B/20, BLys, THANK, CD257)
      GITR (18, AITR, CD357)TRAF1–5GITRL (18, AITRL, TL6)
      TROY (19, TAJ)TRAF2, TRAF5, TRAF6?
      RELT (19L)TRAF1?
      XEDAR (27)TRAF3, TRAF6EDA-A2
    Decoy receptorsn/a
      TRAILR3 (10C, DcR1, CD263)TRAIL/Apo2L (10, CD253)
      TRAILR4 (10D, DcR2, CD264)TRAIL/Apo2L (10, CD253)
      OPG (11B)TRAIL/Apo2L (10, CD253), RANKL (11, TRANCE,
      DcR3 (6B)FasL (6), TL1A (15, VEGI), LIGHT (14, CD258)