 |
PDBsum entry 2id5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Ligand binding protein,membrane protein
|
PDB id
|
|
|
|
2id5
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The structure of the lingo-1 ectodomain, A module implicated in central nervous system repair inhibition.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
J Biol Chem, 2006,
281,
36378-36390.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
