The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition.
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.
Mosyak
Lidia
L
Department of Chemical and Screening sciences, Wyeth Research, Cambridge, Massachusetts 02140, USA. lmosyak@wyeth.com
Wood
Andrew
A
Dwyer
Brian
B
Buddha
Madhavan
M
Johnson
Mark
M
Aulabaugh
Ann
A
Zhong
Xiaotian
X
Presman
Eleonora
E
Benard
Susan
S
Kelleher
Kerry
K
Wilhelm
James
J
Stahl
Mark L
ML
Kriz
Ron
R
Gao
Ying
Y
Cao
Zixuan
Z
Ling
Huai-Ping
HP
Pangalos
Menelas N
MN
Walsh
Frank S
FS
Somers
William S
WS
D000818:Animals; D001369:Axons / Q000378:metabolism; D001703:Biophysics / Q000379:methods; D016466:CHO Cells; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002490:Central Nervous System / Q000293:injuries* / Q000473:pathology*; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D009186:Myelin Sheath / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D017434:Protein Structure, Tertiary
C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D007930:Leucine