Structural Characterization of the p75 Neurotrophin Receptor: A Stranger in the TNFR Superfamily

Although p75 neurotrophin receptor (p75^NTR) was the founding member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF), it is an atypical TNFRSF protein. p75^NTR like TNF-R1 and Fas-R contain an extracellular domain with four cysteine-rich domains (CRD) and a death domain (DD) in the intracellular region. While TNFRSF proteins are activated by trimeric TNFSF ligands, p75^NTR forms dimers activated by dimeric neurotrophins that are structurally unrelated to TNFSF proteins. In addition, although p75^NTR shares with other members the interaction with the TNF receptor-associated factors to activate the NF-κB and cell death pathways, p75^NTR does not interact with the DD-containing proteins FADD, TRADD, or MyD88. By contrast, the DD of p75^NTR is able to recruit several protein interactors via a full catalog of DD interactions not described before in the TNFRSF. p75-DD forms homotypic symmetrical DD-DD complexes with itself and with the related p45-DD; forms heterotypic DD-CARD interactions with the RIP2-CARD domain, and forms a new interaction between a DD and RhoGDI. All these features, in addition to its promiscuous interactions with several ligands and coreceptors, its processing by α- and γ-secretases, the dimeric nature of its transmembrane domain and its "special" juxtamembrane region, make p75^NTR a truly stranger in the TNFR superfamily. In this chapter, I will summarize the known structural aspects of p75^NTR and I will analyze from a structural point of view, the similitudes and differences between p75^NTR and the other members of the TNFRSF.