2mjo | pdb_00002mjo
NMR structure of p75 transmembrane domain C257A mutant in DPC micelles
Structural highlights
Function[TNR16_RAT] Plays a role in the regulation of the translocation of GLUT4 to the cell surface in adipocytes and skeletal muscle cells in response to insulin, probably by regulating RAB31 activity, and thereby contributes to the regulation of insulin-dependent glucose uptake (By similarity). Low affinity receptor which can bind to NGF, BDNF, NT-3, and NT-4. Can mediate cell survival as well as cell death of neural cells. Publication Abstract from PubMedDimerization of single span transmembrane receptors underlies their mechanism of activation. p75 neurotrophin receptor plays an important role in the nervous system, but the understanding of p75 activation mechanism is still incomplete. The transmembrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signaling. Here we solved by NMR the three-dimensional structure of the p75-TM-WT and the functionally inactive p75-TM-C257A dimers. Upon reconstitution in lipid micelles, p75-TM-WT forms the disulfide-linked dimers spontaneously. Under reducing conditions, p75-TM-WT is in a monomer-dimer equilibrium with the Cys(257) residue located on the dimer interface. In contrast, p75-TM-C257A forms dimers through the AXXXG motif on the opposite face of the alpha-helix. Biochemical and cross-linking experiments indicate that AXXXG motif is not on the dimer interface of p75-TM-WT, suggesting that the conformation of p75-TM-C257A may be not functionally relevant. However, rather than mediating p75 homodimerization, mutagenesis of the AXXXG motif reveals its functional role in the regulated intramembrane proteolysis of p75 catalyzed by the gamma-secretase complex. Our structural data provide an insight into the key role of the Cys(257) in stabilization of the weak transmembrane dimer in a conformation required for the NGF signaling. Structural Basis of p75 Transmembrane Domain Dimerization.,Nadezhdin KD, Garcia-Carpio I, Goncharuk SA, Mineev KS, Arseniev AS, Vilar M J Biol Chem. 2016 Jun 3;291(23):12346-57. doi: 10.1074/jbc.M116.723585. Epub 2016, Apr 7. PMID:27056327[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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