title: Structural Characterization of the p75 Neurotrophin Receptor: A Stranger in the TNFR Superfamily.
abstract: Although p75 neurotrophin receptor (p75NTR) was the founding member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF), it is an atypical TNFRSF protein. p75NTRlike 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, p75NTRforms dimers activated by dimeric neurotrophins that are structurally unrelated to TNFSF proteins. In addition, although p75NTRshares with other members the interaction with the TNF receptor-associated factors to activate the NF-κB and cell death pathways, p75NTRdoes not interact with the DD-containing proteins FADD, TRADD, or MyD88. By contrast, the DD of p75NTRis 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 p75NTRa truly stranger in the TNFR superfamily. In this chapter, I will summarize the known structural aspects of p75NTRand I will analyze from a structural point of view, the similitudes and differences between p75NTRand the other members of the TNFRSF.
authors.affiliation: Molecular Basis of Neurodegeneration Unit, Institute of Biomedicine of Valencia (IBV-CSIC), València, Spain. Electronic address: mvilar@ibv.csic.es.
authors.forename: M
authors.initials: M
authors.lastname: Vilar
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008024:Ligands; D009414:Nerve Growth Factors; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D000099183:Sortilin; C415902:TNFRSF1B protein, human
keywords: NGF; NMR; NRH2; Neurotrophin; RIP2; Sortilin; Transmembrane domain dimer; TrkA; X-Ray crystallography; p75