PMID: 17005555

 

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

Abstract :
  1. Nogo receptor ( NgR )-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1
  2. Interactions between Lingo-1 and NgR , along with a complementary co-receptor , result in neurite and axonal collapse
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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