The Structure of the Lingo-1 Ectodomain, a Module Implicated in Central Nervous System Repair Inhibition.
From: Department of Chemical and Screening sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. lmosyak@wyeth.com
The Journal of biological chemistry
- Publish Date: Nov 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 47
- Pages: 36378-90
- Medium: Print
- Language: English
- Citation (JAMA): Mosyak Lidia, Wood Andrew, Dwyer Brian, et al. The Structure of the Lingo-1 Ectodomain, a Module Implicated in Central Nervous System Repair Inhibition.. J. Biol. Chem. Nov 2006;281:36378-90
Abstract
Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 A2) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane.
Mesh Headings (Keywords): Animals, Axons, Biophysics, CHO Cells, Cell Differentiation, Cell Membrane, Central Nervous System, Cricetinae, Crystallography, X-Ray, Humans, Leucine, Membrane Proteins, Myelin Sheath, Nerve Tissue Proteins, Oligodendroglia, Protein Structure, Tertiary
Check for Full Text / PubMed Unique Identifier (PMID): 17005555
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