A Structural and Functional Perspective of Death Receptor 6

Abstract

As a member of the tumor necrosis factor receptor superfamily (TNFRSF), death receptor 6 (DR6) has a similar structural architecture to other family members. The extracellular region of DR6 contains four cysteine-rich domains, followed by a single-pass transmembrane domain and an intracellular region. Since its discovery, DR6 has become an orphan receptor ubiquitously expressed to transduce unique signaling pathways. Although the free ectodomains of β-amyloid precursor protein (APP) can bind to DR6 to induce apoptotic signals, the natural ligands of DR6 still remain largely unknown. In this review, we focus on recent research progress of structural and functional studies on DR6 for better understanding DR6-mediated signaling and the treatment of DR6-related diseases.

Keywords: DR6; co-receptor; death domain; death receptor; signaling.

FIGURE 1

The structure of DR6 (A) Molecular architecture of human DR6. SP: signal peptide; CRD: cysteine-rich domain; TM: transmembrane sequence; DD: death domain; CARD: caspase activation and recruitment domain. (B) Amino acid sequence of full-length human DR6. The secondary structures of DR6 are shown below the sequence. The red letters indicate the structured elements. N-glycosylation sites are colored in blue and underlined; O-glycosylation sites, green and underlined. A putative leucine zipper motif with a proline-rich sequence is green underlined (C) Ribbon drawing of crystal structure of the DR6-CRDs (PDB ID: 3QO4) (D) Structural comparison between CRDs of DR6 (green) and DcR3 (purple, PDB ID: 3MHD) (E) Structural model of the DR6-TMD. (F) Structural comparison between monomeric TMDs of DR6 (cyan) and p75^NTR (dark green, left, PDB ID: 2MIC)/TNFR1(orange, right, PDB ID: 7K7A) (G) Structural model of the DR6-DD. (H) Structural comparison between DDs of DR6 (blue) and p75^NTR (yellow, PDB ID: 4F42) (I) Ribbon drawing of the lowest energy structure of C-terminal CARD domain of DR6 (PDB ID: 2DBH) (J) Structural comparison between CARDs of DR6 (green) and Nod1 (dark red, PDB ID: 2NZ7).

FIGURE 2

Complex structure between DR6-CRDs and APP-E2 (PDB ID:4YN0) (A). APP-E2 domain is colored in cyan, and CRDs of DR6 are colored in green. (B). Structural comparison between monomeric DR6-CRDs (purple) and the DR6-CRDs (green) from DR6-CRDs:APP-E2 complex.

FIGURE 3

Cartoon models of DR6 signaling (A) DR6-mediated intracellular signaling pathways are showed in four different cells, brain endothelial cell, neurons, HeLa, and HEK293T. In brain endothelial cell, DR6 and TROY complex is involved in angiogenesis and BBB formation. They are regulated by Wnt/β-catenin signaling and engage in crosstalk with the VEGF/VEGFR2 signaling pathway. In neuron cells, DR6 can interact with APP or p75^NTR to promote neuronal apoptosis and axonal degeneration. In HeLa cells, DR6 can promote mitochondria-dependent apoptosis through membrane protein PSAP. In HEK293T, DR6 can induce NF-kB pathway and promote cell survival through adaptor protein TRADD. (B) Extracellular signaling pathway of sDR6. In MCF-7 cancer cell line, cleavage of the extracellular region of DR6 by the metalloenzyme MMP-14 leads to the formation of sDR6. This soluble protein can hinder the differentiation of monocytes into immature dendritic cells, thereby inhibiting the body’s immune response. In neurons, sDR6 produced by metalloprotease ADAM10 cleavage can trans-act on Schwann cells and inhibit their proliferation and myelination in the PNS. The intracellular domain is released into the cytosol and rapidly degraded by proteasome.