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Structure of the C-Terminal Domain of TRADD Reveals a Novel Fold in The www.nature.com/scientificreports OPEN Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily Received: 20 March 2017 Ning Zhang1, Wensu Yuan1, Jing-Song Fan2 & Zhi Lin 1,3,4 Accepted: 27 June 2017 The TNFR1-associated death domain protein (TRADD) is an intracellular adaptor protein involved in Published online: 1 August 2017 various signaling pathways, such as antiapoptosis. Its C-terminal death domain (DD) is responsible for binding other DD-containing proteins including the p75 neurotrophin receptor (p75NTR). Here we present a solution structure of TRADD DD derived from high-resolution NMR spectroscopy. The TRADD DD comprises two super-secondary structures, an all-helix Greek key motif and a β-hairpin motif fanked by two α helices, which make it unique among all known DD structures. The β-hairpin motif is essential for TRADD DD to fold into a functional globular domain. The highly-charged surface suggests a critical role of electrostatic interactions in TRADD DD-mediated signaling. This novel structure represents a new class within the DD superfamily and provides a structural basis for studying homotypic DD interactions. NMR titration revealed a direct weak interaction between TRADD DD and p75NTR DD monomers. A binding site next to the p75NTR DD homodimerization interface indicates that TRADD DD recruitment to p75NTR requires separation of the p75NTR DD homodimer, explaining the mechanism of NGF-dependent activation of p75NTR-TRADD-mediated antiapoptotic pathway in breast cancer cell. Te death domain (DD) superfamily is one of the largest collection of structurally and functionally related pro- tein interaction modules. DD-containing proteins play key roles in the activation of apoptotic, innate immunity and infammatory signaling through the formation of oligomeric protein complexes with receptors, kinases and other proteins1, 2. DD-mediated signaling pathways are related to many important human diseases, hence a better understanding of their structure and function is of great biological importance. Te DD superfamily comprises four subfamilies of domains with closer structural similarity, including the canonical DD, the death efector domain (DED), the caspase recruitment domain (CARD) and the pyrin domain (PYD)3. Members of the DD superfamily share a common structural fold, namely an isolated antiparallel helix bundle. Nevertheless, individ- ual members exhibit diferent structural characteristics, including varied helix length and orientation as well as highly diverse electrostatic surfaces, a feature that is critical for the binding specifcity of DDs4, 5. DDs are present in a wide range of proteins, including several members of the tumor necrosis factor recep- tor (TNFR) superfamily and various intracellular signaling molecules, such as caspases and kinases6. The TNFR1-associated death domain protein (TRADD) is a multifunctional 34-kDa adaptor protein, consisting of two structurally distinct domains connected by a long linker peptide of 37 amino acid residues7–10. Its N-terminal domain folds into an α/β sandwich structure while its carboxyl-terminal domain is a DD (TRADD DD)8, 9. TRADD has several protein binding partners and participates in diferent signaling pathways, including NF-κB, apoptosis, necrosis and mitogen-activated protein (MAP) kinase activation10, 11. It binds to TNFR1 in a TNF dependent manner and serves as a platform to recruit additional proteins7. Te N-terminal domain of TRADD interacts with the C-terminal domain of TNFR-associated factor 2 (TRAF2) and recruits TRAF2 to TNFR1 for activation of the NF-κB pathway8, 12. On the other hand, the TRADD DD interacts with other DD-containing proteins through homotypic DD-DD interactions. TRADD DD directly binds the DD of TNFR17. It can also simultaneously bind to the DD of Fas-associated protein with death domain (FADD) to recruit FADD to TNFR1 for initiation of the apoptototic cascade13. It has been reported that TRADD can associate with the p75NTR in (MCF-7) breast cancer cells upon receptor activation by neurotrophins (NT)14. Te involvement of TRADD in 1School of Life Sciences, Tianjin University, Tianjin, 300072, P.R. China. 2Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore. 3Department of Physiology, National University of Singapore, Singapore, 117593, Singapore. 4Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore. Correspondence and requests for materials should be addressed to Z.L. (email: linzhi@linzhi. net) SCIENTIFIC REPORTS | 7: 7073 | DOI:10.1038/s41598-017-07348-9 1 www.nature.com/scientificreports/ NMR distance & dihedral constraints Distance constraints Total NOE 2990 Intra-residue 1171 Inter-residue Sequential (|i-j| = 1) 664 Medium-range (|i-j| ≤4) 608 Long-range (|i-j| ≥5) 547 Total dihedral angle straintsa 180 Structure Statistics Violations (mean and s.d.) Distance constraints (Å) 0.30 ± 0.02 Dihedral angle constraints (°) 3.78 ± 0.24 Max. dihedral angle violation (°) 4.30 Max. distance constraint violation (Å) 0.37 Ramachandran Plotb Most favored regions 90.7% Addtional allowed regions 9.3% Generously allowed regions 0.0% Disallowed regions 0.0% Average RMSD (Å)c Heavy atoms 0.70 ± 0.05 Backbone atoms 0.22 ± 0.05 Table 1. NMR and refnement statistics TRADD DD. aDihedral angle constraints were generated by TALOS+ based on Cα and Cβ chemical shifs. bAs determined by PROCHECK NMR in the ordered region of 201–304. cAverage r.m.s. deviation (RMSD) to the mean structure was calculated among 10 refned structures. Superimposed residues are 201–304. Te total AMBER energy is −5175.88 ± 21 kcal/mol. p75NTR signaling was shown to be required for NF-κB activation and control of antiapoptotic efects of neurotro- phins in breast cancer cells. Upon TRADD depletion, p75NTR was reported to induce cell death in conditionally immortalized striatal neurons15. Tese studies suggest that TRADD is crucial for balancing antiapoptotic and proapoptotic signaling pathways. Te structure of human TRADD DD has previously been determined by nuclear magnetic resonance (NMR) technique under an acidic condition of pH 4.29, 16. However, its structure fle is unavailable. At pH 4.2, TRADD DD adopt a characteristic DD fold, but the residues A199-S215 in its N terminus were completely disordered in solution9. Here, we present a diferent NMR solution structure of human TRADD DD in pure water, revealing a structure not previously seen in the DD superfamily and providing a better structural basis for studying TRADD DD-mediated signaling. Results and Discussion NMR Solution Structure Determination of TRADD DD. Te structure of monomeric TRADD DD was determined by a total of 2990 nuclear Overhauser efect (NOE)-based distance restraints, including 547 long-range NOEs, which were obtained using uniformly 15N- and 15N/13C-labeled proteins with double and triple resonance NMR experiments. Te structural statistics and root-mean-square deviation (RMSD) are in Table 1, and the superposition of the ensemble of 10 structures with lowest energy is shown in Fig. 1A. Although the C-terminal tail of residues T305-A312 is disordered, the globular domain of TRADD DD was defned with high precision. RMSD to the mean coordinate for residues T201-L304 is 0.22 ± 0.05 Å for the backbone atoms and 0.70 ± 0.05 Å for all atoms. Tis fne result can be attributed to ~28 NOE distance constraints per residue obtained in the 104-residue globular structure of TRADD DD (Table 1 and Fig. S1), for which nearly complete chemical shifs have been assigned. Ramachandran plot analysis of ordered regions placed 90.7% of residues in the “most favored regions” with 9.3% of residues in the “additional allowed regions” and no residue in the “generously allowed region” or “disallowed region”. Global quality Z scores were −1.28, 0.21, −0.12 and −1.38 for Verify3D, ProsaII(−ve), Procheck (phi-psi) and MolProbity Clashscore, respectively, indicating a good-quality structure of TRADD DD at the atomic level. Novel Structure of TRADD DD. Te solution structure of TRADD DD is composed of two antiparal- lel β-strands, six antiparallel α-helices and a short three-residue 310-helix between helices α2 and α3 (Fig. 1B). Detailed inspection of the domain structure reveals that TRADD DD comprises two major super-secondary structures, a Greek key motif made of fve α-helices (α1, α2, α3, α4 and α5) and a β-hairpin motif (β1 and β2) fanked by helices α5 and α6. Te two motifs are tightly packed together to form four distinct hydrophobic cores (Fig. 1C). Te packing of β1, β2, α5 and α6 forms the frst bundle with a hydrophobic core (C1). A number of long-range and tertiary hydrophobic interactions from Leu, Val, Phe, and Ala are involved in the formation and stabilization of C1 (Fig. 1D and Fig. S2). Helix α1 together with α5 and α6 form a central bundle and a central SCIENTIFIC REPORTS | 7: 7073 | DOI:10.1038/s41598-017-07348-9 2 www.nature.com/scientificreports/ Figure 1. Solution structure of TRADD DD. (A) Superposition of the backbone heavy atoms of the ten lowest- energy structures of TRADD DD. (B) Ribbon drawing of the lowest-energy conformer of TRADD DD. (C) Four structurally distinct hydrophobic cores in TRADD. Core 1 (C1, green) is formed by a β-hairpin, helices α5 and α6; core 2 (C2, purple) and core 3 (C3, blue) are two central cores formed by three (α1, α5 and α6) and four (α1, α2, α4 and α5) helices, respectively; core 4 (C4, brown) is packed by helices α2, α3 and α4. (D) Hydrophobic core 1 involves 8 hydrophobic residues from one pair of β strands and one pair of α helices. hydrophobic core (C2). Te other central bundle is made of two pairs of parallel helices (α1/α5 and α2/α4) that are packed approximately orthogonally to form the third hydrophobic core (C3). Te last hydrophobic core (C4) is formed by three contiguous helices α2, α3 and α4.
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