2026-06-14T05:05:40Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/96682025-06-13T10:29:39Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617
Repisalud
author
Nadezhdin, Kirill D
author
Garcia-Carpio, Irmina
author
Goncharuk, Sergey A
author
Mineev, Konstantin S
author
Arseniev, Alexander S
author
Vilar, Marçal
funder
Ministerio de Economía y Competitividad (España)
2020-04-21T14:41:21Z
2020-04-21T14:41:21Z
2016-06-03
J Biol Chem . 2016 Jun 3;291(23):12346-57.
10.1074/jbc.M116.723585
1083-351X
0021-9258
The Journal of biological chemistry
27056327
http://hdl.handle.net/20.500.12105/9668
Dimerization 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 α-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 γ-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.
eng
Dimerization
Neurotrophin
Nuclear magnetic resonance (NMR)
p75 neurotrophin receptor
Transmembrane domain
γ-secretase
Structural Basis of p75 Transmembrane Domain Dimerization
research article
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https://repisalud.isciii.es/bitstreams/5809261d-2b1a-4375-9cd6-448945c97dff/download
File
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953b886883c41a600e999855190e1573
2405860
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StructuralBasisOfP75_2016.pdf
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https://repisalud.isciii.es/bitstreams/8eeddf7a-bfd9-4acb-bf2a-9900420801f8/download
File
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6f066094831c1d9b4e6a63e7d70082d0
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text/plain
StructuralBasisOfP75_2016.pdf.txt