Structure of TRAF Family: Current Understanding of Receptor Recognition

Abstract

Tumor necrosis factor receptor-associated factor (TRAF) proteins are key signaling molecules that function in various cellular signaling events including immune response, cell death and survival, development, and thrombosis. Their roles in cellular signaling are mediated mostly by direct interactions with various receptors via the TRAF domain. To determine how specific TRAF domains can interact with various receptors with a limited binding interface and how similar binding interfaces of TRAF family members can recognize their specific binding partners, extensive structural studies on TRAF family proteins have been conducted for several decades. In this review, we discuss the current understanding of the structural and molecular diversity of the TRAF domain and TRAF-binding motifs in many receptors according to available structural information.

Keywords: TRAF domain; TRAF family; inflammation; innate immunity; protein interaction; structure.

Figure 1

Structure of the TRAF family. (A) The domain boundary in TRAF family members. (B) A cartoon of the monomeric TRAF domain. The representative TRAF domain of TRAF1 is used to show the overall structure of this domain. The chain from the N to C terminus is colored blue to red. Secondary structures including helices and sheets are labeled. (C) Superposition of the structures of the TRAF domain. (D) Electrostatic surface representation of the TRAF domain in the TRAF family. PyMol (https://www.pymol.org/) was used to compute qualitative surface electrostatic potential. The receptor-binding region in a TRAF family member is indicated by the black dotted circle. (E) A cartoon of the trimeric TRAF domain. Different chains are shown separately in different colors. The top view (upper panel) and side view (lower panel) are presented. The asterisks indicate the receptor-binding region. (F) A model of the full-length structure of TRAF family members.

Figure 2

The TRAF-binding motif identified by structures of TRAF–receptor complexes. (A) Receptor-binding hot spots and conserved amino acid residues (in TRAF1, −2, −3, and −5) that are involved in the interaction with various receptors. The amino acid residues in TRAF4 and −6 that are not conserved are colored in red. (B–E) Detailed TRAF–receptor interaction. Close-up view of a CD40 peptide bound to TRAF2 (B), a TANK peptide bound to TRAF3 (C), a GPIbβ peptide bound to TRAF4 (D), and a RANK peptide bound to TRAF6 (E). Red dotted lines and black dotted lines indicate salt bridges and H-bonds, respectively. Amino acid positions of the peptide labeled as P₋₄-P₃ are shown. TRAF-binding motifs are shown. (F) Structural comparison of the TRAF–receptor peptide complex by superposition analysis.