Leucine rich repeat and Immunoglobin-like domain-containing protein 1 also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans. It belongs to the family of leucine-rich repeat proteins which are known for playing key roles in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo (neurite outgrowth inhibitor) receptor also known as the reticulon 4 receptor.
It has been suggested that LINGO-1 antagonists such as BIIB033 could significantly improve and regulate survival after neural injury caused by the protein.
Structure
The human LINGO-1 is a single-pass type 1 transmembrane protein of 614 amino acids. It contains a signal sequence of 34 residues, followed by a LRR (leucine-rich repeat) domain, an Ig (immunoglobulin-like) domain, a stalk domain, a transmembrane region and a short cytoplasmic tail. As a transmembrane protein, it can mostly be found on the cell membrane.
The LINGO-1 structure has been shown to be highly stable both in its crystal form and in solution, thanks to its leucine-rich repeat Ig-composite fold. Since the tetramer has a very large surface area into the cell membrane, it is thought that this may serve as an efficient and stable binding platform, facilitating the interaction with NgR, p75, TROY complex.
Extracellular domain
The extracellular domain consists of the signal sequence, 11 LRR motifs comprised between an N-terminal and C-terminal capping domains, and the Immunoglobulin-like (IgC2) domain. The C-terminal LRR domain is essential for the protein's function with its screening for proteins that interact with this domain. The structure, together with biophysical analysis of LINGO-1 properties have revealed that the protein's LRR-Ig composite fold of the protein can drive it to associate with itself in a circular ring-like form, creating a closed and stable tetramer in solution and in crystal.
Intracellular domain
The intracellular part of the protein is formed by the transmembrane region and a cytoplasmic tail of 38 residues. It contains a canonical Epidermal Growth Factor Receptor (EGFR)-like tyrosine phosphorylation site on the 591 residue that is critical for intracellular signals.
Co-receptor
LINGO-1 is a co-receptor that interacts with the ligand-binding Nogo-66 receptor (NogoR) in the Nogo receptor signaling complex. The Nogo receptor complex is formed when Nogo-66 binds to its receptor.
LINGO-1 is an homotetramer which forms a ternary complex with RTN4R/NGFR and RTN4R/TNFRSF19.
Post-translational modifications
LINGO-1 contains several N-glycosylation sites that could have a negative effect on its capacity to self-interact with cis or trans, with other partners, or gangliosides. It also contains high-mannose glycans.
Tissue distribution
LINGO-1 is expressed almost exclusively in the central nervous system (CNS). It can be found in the brain and in neurons and oligodendrocytes. LINGO-1 mRNA is expressed in an almost exclusive manner in the central nervous system during both embryonic and postnatal stages. It is targeted to the plasma membrane of neurons, but it is possible that a smaller quantities of the protein may be found in other intracellular compartments. Its highest expression is in specific adult human brain regions such as the cerebral cortex, a region involved in sensory-motor function, cognition and working memory; the hippocampus, responsible for long-term memory and the encoding and retrieval of multi-sensory information; the amygdala, implicated in the stress response; as well as the thalamus, with a more constant and basal level of expression across the remainder of the brain.
Function and mode of action
Since LINGO-1 is a leucine-rich repeat protein, which are known for their important role in protein-protein interactions in a wide variety of cellular processes and their implication in important functions like neuronal differentiation and growth or the regulation of axon guidance and regeneration processes, it is logical to deduce that its functions are linked with the nervous system.