Structure of the Nogo receptor ectodomain: A recognition module implicated in myelin inhibition

Xiaolin L. He; J. Fernando Bazan; Gerry McDermott; Jong Bae Park; Kevin Wang; Marc Tessier-Lavigne; Zhigang He; K. Christopher Garcia

doi:10.1016/S0896-6273(03)00232-0

Structure of the Nogo receptor ectodomain: A recognition module implicated in myelin inhibition

Xiaolin L. He, J. Fernando Bazan, Gerry McDermott, Jong Bae Park, Kevin Wang, Marc Tessier-Lavigne, Zhigang He, K. Christopher Garcia^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

185 Scopus citations

Abstract

Failure of axon regeneration in the adult mammalian central nervous system (CNS) is at least partly due to inhibitory molecules associated with myelin. Recent studies suggest that an axon surface protein, the Nogo receptor (NgR), may play a role in this process through an unprecedented degree of crossreactivity with myelin-associated inhibitory ligands. Here, we report the 1.5 Å crystal structure and functional characterization of a soluble extracellular domain of the human Nogo receptor. Nogo receptor adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues, possibly suggestive of degenerate ligand binding sites. A deep cleft at the C-terminal base of the LRR may play a role in NgR association with the p75 coreceptor. These results now provide a detailed framework for focused structure-function studies aimed at assessing the physiological relevance of NgR-mediated protein-protein interactions to axon regeneration inhibition.

Original language	English (US)
Pages (from-to)	177-185
Number of pages	9
Journal	Neuron
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/S0896-6273(03)00232-0
State	Published - Apr 24 2003

Funding

The authors gratefully acknowledge Ben Barres for helpful discussions and Sharon Radoc for technical assistance. The authors also acknowledge the Stanford Synchrotron Radiation Laboratory (SSRL) and the Advanced Light Source (UC-Berkeley) for X-ray resources. The work was funded by grants from the Rita Allen Foundation, Pew Trust, NIH, and AHA (K.C.G. and X.L.H.); and from the NIH, International Spinal Research Trust, the EJLB Foundation, Whitehall Foundation, and The John Merck Fund (Z.H.).

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0896-6273(03)00232-0

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title = "Structure of the Nogo receptor ectodomain: A recognition module implicated in myelin inhibition",

abstract = "Failure of axon regeneration in the adult mammalian central nervous system (CNS) is at least partly due to inhibitory molecules associated with myelin. Recent studies suggest that an axon surface protein, the Nogo receptor (NgR), may play a role in this process through an unprecedented degree of crossreactivity with myelin-associated inhibitory ligands. Here, we report the 1.5 {\AA} crystal structure and functional characterization of a soluble extracellular domain of the human Nogo receptor. Nogo receptor adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues, possibly suggestive of degenerate ligand binding sites. A deep cleft at the C-terminal base of the LRR may play a role in NgR association with the p75 coreceptor. These results now provide a detailed framework for focused structure-function studies aimed at assessing the physiological relevance of NgR-mediated protein-protein interactions to axon regeneration inhibition.",

author = "He, {Xiaolin L.} and Bazan, {J. Fernando} and Gerry McDermott and Park, {Jong Bae} and Kevin Wang and Marc Tessier-Lavigne and Zhigang He and Garcia, {K. Christopher}",

note = "Funding Information: The authors gratefully acknowledge Ben Barres for helpful discussions and Sharon Radoc for technical assistance. The authors also acknowledge the Stanford Synchrotron Radiation Laboratory (SSRL) and the Advanced Light Source (UC-Berkeley) for X-ray resources. The work was funded by grants from the Rita Allen Foundation, Pew Trust, NIH, and AHA (K.C.G. and X.L.H.); and from the NIH, International Spinal Research Trust, the EJLB Foundation, Whitehall Foundation, and The John Merck Fund (Z.H.).",

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T2 - A recognition module implicated in myelin inhibition

AU - He, Xiaolin L.

AU - Bazan, J. Fernando

AU - McDermott, Gerry

AU - Park, Jong Bae

AU - Wang, Kevin

AU - Tessier-Lavigne, Marc

AU - He, Zhigang

AU - Garcia, K. Christopher

N1 - Funding Information: The authors gratefully acknowledge Ben Barres for helpful discussions and Sharon Radoc for technical assistance. The authors also acknowledge the Stanford Synchrotron Radiation Laboratory (SSRL) and the Advanced Light Source (UC-Berkeley) for X-ray resources. The work was funded by grants from the Rita Allen Foundation, Pew Trust, NIH, and AHA (K.C.G. and X.L.H.); and from the NIH, International Spinal Research Trust, the EJLB Foundation, Whitehall Foundation, and The John Merck Fund (Z.H.).

PY - 2003/4/24

Y1 - 2003/4/24

N2 - Failure of axon regeneration in the adult mammalian central nervous system (CNS) is at least partly due to inhibitory molecules associated with myelin. Recent studies suggest that an axon surface protein, the Nogo receptor (NgR), may play a role in this process through an unprecedented degree of crossreactivity with myelin-associated inhibitory ligands. Here, we report the 1.5 Å crystal structure and functional characterization of a soluble extracellular domain of the human Nogo receptor. Nogo receptor adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues, possibly suggestive of degenerate ligand binding sites. A deep cleft at the C-terminal base of the LRR may play a role in NgR association with the p75 coreceptor. These results now provide a detailed framework for focused structure-function studies aimed at assessing the physiological relevance of NgR-mediated protein-protein interactions to axon regeneration inhibition.

AB - Failure of axon regeneration in the adult mammalian central nervous system (CNS) is at least partly due to inhibitory molecules associated with myelin. Recent studies suggest that an axon surface protein, the Nogo receptor (NgR), may play a role in this process through an unprecedented degree of crossreactivity with myelin-associated inhibitory ligands. Here, we report the 1.5 Å crystal structure and functional characterization of a soluble extracellular domain of the human Nogo receptor. Nogo receptor adopts a leucine-rich repeat (LRR) module whose concave exterior surface contains a broad region of evolutionarily conserved patches of aromatic residues, possibly suggestive of degenerate ligand binding sites. A deep cleft at the C-terminal base of the LRR may play a role in NgR association with the p75 coreceptor. These results now provide a detailed framework for focused structure-function studies aimed at assessing the physiological relevance of NgR-mediated protein-protein interactions to axon regeneration inhibition.

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Structure of the Nogo receptor ectodomain: A recognition module implicated in myelin inhibition

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