title: Heterodimerization of p45-p75 modulates p75 signaling: structural basis and mechanism of action.
abstract: The p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily, is required as a co-receptor for the Nogo receptor (NgR) to mediate the activity of myelin-associated inhibitors such as Nogo, MAG, and OMgp. p45/NRH2/PLAIDD is a p75 homologue and contains a death domain (DD). Here we report that p45 markedly interferes with the function of p75 as a co-receptor for NgR. P45 forms heterodimers with p75 and thereby blocks RhoA activation and inhibition of neurite outgrowth induced by myelin-associated inhibitors. p45 binds p75 through both its transmembrane (TM) domain and DD. To understand the underlying mechanisms, we have determined the three-dimensional NMR solution structure of the intracellular domain of p45 and characterized its interaction with p75. We have identified the residues involved in such interaction by NMR and co-immunoprecipitation. The DD of p45 binds the DD of p75 by electrostatic interactions. In addition, previous reports suggested that Cys257 in the p75 TM domain is required for signaling. We found that the interaction of the cysteine 58 of p45 with the cysteine 257 of p75 within the TM domain is necessary for p45-p75 heterodimerization. These results suggest a mechanism involving both the TM domain and the DD of p45 to regulate p75-mediated signaling.
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, United States of America; Neurodegeneration Unit, Chronic Disease Program, Spanish Institute of Health Carlos III, Madrid, Spain.
authors.forename: Marçal
authors.initials: M
authors.lastname: Vilar
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, United States of America.
authors.forename: Tsung-Chang
authors.initials: TC
authors.lastname: Sung
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, United States of America.
authors.forename: Zhijiang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Neurodegeneration Unit, Chronic Disease Program, Spanish Institute of Health Carlos III, Madrid, Spain.
authors.forename: Irmina
authors.initials: I
authors.lastname: García-Carpio
authors.affiliation: Neurodegeneration Unit, Chronic Disease Program, Spanish Institute of Health Carlos III, Madrid, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Fernandez
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, United States of America.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, United States of America; Laboratory for Physical Chemistry, ETH Zürich, Zürich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California, United States of America.
authors.forename: Kuo-Fen
authors.initials: KF
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D055550:Protein Stability; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D015398:Signal Transduction; D012996:Solutions; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: C476128:NRH2 protein, mouse; D020800:Receptor, Nerve Growth Factor; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D012996:Solutions; D003545:Cysteine
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