Title : The
structure of the Lingo-1 ectodomain , a module implicated in central nervous system repair inhibition
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 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