Death domain of p75 neurotrophin receptor: a structural perspective on an intracellular signalling hub

Abstract

The death domain (DD) is a globular protein motif with a signature feature of an all-helical Greek-key motif. It is a primary mediator of a variety of biological activities, including apoptosis, cell survival and cytoskeletal changes, which are related to many neurodegenerative diseases, neurotrauma, and cancers. DDs exist in a wide range of signalling proteins including p75 neurotrophin receptor (p75 NTR ), a member of the tumour necrosis factor receptor superfamily. The specific signalling mediated by p75 NTR in a given cell depends on the type of ligand engaging the extracellular domain and the recruitment of cytosolic interactors to the intracellular domain, especially the DD, of the receptor. In solution, the p75 NTR -DDs mainly form a symmetric non-covalent homodimer. In response to extracellular signals, conformational changes in the p75 NTR extracellular domain (ECD) propagate to the p75 NTR -DD through the disulfide-bonded transmembrane domain (TMD) and destabilize the p75 NTR -DD homodimer, leading to protomer separation and exposure of binding sites on the DD surface. In this review, we focus on recent advances in the study of the structural mechanism of p75 NTR -DD signalling through recruitment of diverse intracellular interactors for the regulation and control of diverse functional outputs.

Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

“…Several studies have unraveled the roles of p75 NTR structural domains in the activation of death receptor signaling. The extracellular domain of p75 NTR appears to be responsible for the conformational changes that propagate the signal to its death domain, which further recruits the interactors of various signaling pathways [81][82][83]. The death domain is also necessary for p75 NTR -induced neuronal apoptosis [83,84].…”

“…The extracellular domain of p75 NTR appears to be responsible for the conformational changes that propagate the signal to its death domain, which further recruits the interactors of various signaling pathways [81][82][83]. The death domain is also necessary for p75 NTR -induced neuronal apoptosis [83,84]. The induction of apoptosis is dependent on the N-terminal domain that was shown to be modified by N-glycosylation, i.e., the attachment of an oligosaccharide to the protein in the ER [27].…”

Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

“…[4] Similar to other TNFRSF members, p75 NTR does not have intrinsic catalytic activity, and its signaling depends on the recruitment of intracellular interactors. [5]…”

“…p75 NTR consists of an extracellular cysteine-rich domain (ECD), a single-pass transmembrane domain (TMD) involved in the formation of an intermolecular disulfide bridge, and an intracellular domain (ICD), containing an unstructured juxtamembrane domain (JMD) and a helical death domain (DD). [5]–[6] Upon binding extracellular signals, such as the neurotrophin nerve growth factor (NGF), the p75 NTR -ECD undergoes significant conformational changes from an open to a closed state. [7] This movement further propagates to the p75 NTR -DD through the disulfide-bonded p75 NTR -TMD, leading to separation of the p75 NTR -DD homodimer and exposure of active sites on the p75 NTR -DD surface for recruitment of DD interactors.…”

“…[8] As a signaling hub, the p75 NTR -DD has been shown to interact with various intracellular molecules to regulate different signaling cascades, including NF-κB, RhoA, and JNK/caspase pathways in diverse cellular contexts. [5, 9] Among the many proteins that interact with the p75 NTR -ICD, TRADD (TNF receptor associated death domain) is rather unique due to its ability to create a platform on the membrane for recruitment of additional proteins for downstream signaling. [10] TRADD is a 34 kDa protein with two functional domains (N- and C-terminal domains) connected by an unstructured peptide of ~38 amino acids.…”