The Structure of the Lingo-1 Ectodomain, a Module Implicated in Central Nervous System Repair Inhibition

Lidia Mosyak, Andrew Wood, Brian Dwyer, Madhavan Buddha, Mark Johnson, Ann Aulabaugh, Xiaotian Zhong, Eleonora Presman, Susan Benard, Kerry Kelleher, James Wilhelm, Mark L. Stahl (+7 others)
2006 Journal of Biological Chemistry  
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
more » ... r 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 Å 2 ) 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. . 3 The abbreviations used are: MAG, myelin-associated glycoprotein; NgR, Nogo receptor; LRR, leucine-rich repeat; CHO, Chinese hamster ovary; Bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; r.m.s., root mean square; NCAM, neural cell adhesion molecule; SIRAS, single isomorphous replacement with anomalous scattering.
doi:10.1074/jbc.m607314200 pmid:17005555 fatcat:o45rapzvzza73p7lb4i5ae5bqi