PDBsum entry 2id5

Ligand binding protein,membrane protein

PDB id: 2id5

Contents

Protein chains

470 a.a. *

Ligands

NAG-NAG-MAN ×9

NAG-NAG ×2

NAG-NAG-MAN-MAN ×2

NAG ×13

Waters ×308

* Residue conservation analysis

PDB id:

2id5

Name:

Ligand binding protein,membrane protein

Title:

Crystal structure of the lingo-1 ectodomain

Structure:

Leucine rich repeat neuronal 6a. Chain: a, b, c, d. Fragment: extracelullar portion. Synonym: lingo-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lrrn6a. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: hampster ovary cells.

Resolution:

2.70Å R-factor: 0.216 R-free: 0.255

Authors:

L.Mosyak,A.Wood,B.Dwyer,M.Johnson,M.L.Stahl,W.S.Somers

Key ref:

L.Mosyak et al. (2006). The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J Biol Chem, 281, 36378-36390. PubMed id: 17005555 DOI: 10.1074/jbc.M607314200

Date:

14-Sep-06 Release date: 26-Sep-06

Protein chains

Q96FE5  (LIGO1_HUMAN) -  Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 from Homo sapiens

Seq: 620 a.a.

Struc: 470 a.a.

DOI no: 10.1074/jbc.M607314200

J Biol Chem 281:36378-36390 (2006)

PubMed id: 17005555

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

L.Mosyak, A.Wood, B.Dwyer, M.Buddha, M.Johnson, A.Aulabaugh, X.Zhong, E.Presman, S.Benard, K.Kelleher, J.Wilhelm, M.L.Stahl, R.Kriz, Y.Gao, Z.Cao, H.P.Ling, M.N.Pangalos, F.S.Walsh, W.S.Somers.

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.

Selected figure(s)

Figure 4.
Glycosylation of Lingo-1, front view. The molecular surface of Lingo-1 is shown, colored according to electrostatic potential (red for negative, and blue for positive charges), with the surfaces represented in yellow for carbohydrate. The seven N-linked sugars are labeled. The back side of the molecule (not shown) is carbohydrate-free. The view on the left is tilted to highlight the position of the two N-glycans on the front concave LRR face. Hydrogen bonding is depicted with dashed white lines.

Figure 5.
Structure of the Lingo-1 tetramer. A, view of the top and front surfaces of the Lingo-1 tetramer, rendered in red, green, magenta, and yellow. The two views are related by a 90° rotation about the horizontal axis. Carbohydrate are shown as yellow sticks. The LRR modules interlock the ring head-to-tail, back-to-back, with the IgI1s extend vertically. The bottom view illustrates the putative orientation of the tetramer relative to a cell surface. B, detailed view of molecular interfaces. The imprint of bound LRR (red ribbons) on the molecular surface of a neighboring monomer is colored blue. The top and bottom insets are close-up views of some of the interactions at the LRR-LRR′ and IgI1-LRR′ interfaces, respectively; the prime symbols denote the partner molecule. Molecular surfaces for the two interacting monomers are colored as in A, green and red. Side chains of interacting residues are shown as a ball-and-stick model, and hydrogen bonds are shown with dashed white lines. All interface residues are conserved apart from Ala^461 (Ser in chicken, see also Fig. 7A).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 36378-36390) copyright 2006.

Figures were selected by an automated process.