Neuroligins
http://artedi.ebc.uu.se/course/BioInfo-10p-2006/projects/katarzyna/Neuroligins.html
Actualización: 20/02/2007
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The family of
human neuroligins (NLGN) consists of 5 genes located on chromosomes 3,
17, X (NLGN3, NLGN4X) and Y (NLGN4Y). In rodents 3 genes where
identified. The history of their discovery reflects their binding
properties. Neurexins drew attention because of binding to a component
of black widow venom - alpha-latrotoxin. Humans have 3 genes for
neurexins, all of them equipped in two alternative promoters. The
shorther one - beta-neurexin consists of intracellular region that has
the PDZ interaction site, one transmembrane region and one LNS domain.
LNS stands for laminin, nectin, sex-hormone binding globulin and as
stated by the name is found in many other proteins. The longer protein
is called alpha-neurexin and have 5 additional LNS domains. alpha-neurexins
influence localization and function of Ca2+ channels and NMDA receptors.
Rat neuroligin 1
was discovered by its interaction with beta-neurexin. Following was the
discovery of two other rodent neuroligins (NLGN2,3) and a fourth one
(NLGN4X and NLGN4Y) which seems to be specific for humans. Neurexin
structure has been resolved experimentally (PDB 1C4R). Neuroligins
belong to the a/b hydrolase fold with the highest sequence similarity (about
30% identity) to the enzyme acetylcholinesterase. Both neuroligins and
neurexins are subject to extensive alternative splicing which influences
their binding properties. Unspliced neuroligins bind to beta-neurexins
lacking an insert at the 4 splice site and do not bind alpha-neurexins.
The neuroligin isoform lacking an 8-aa peptide binds both types of
neurexins.
There are crystal structures available
for neurexins: PDB 1T2M (PDZ domain), 1C4R(LNS domain - ligand binding,
Rudenko et al 1999) and 1KWA(PDZ domain).
No experimentally resolved structure is
available for neuroligins.
Rat neuroligins 1,2 and 3 are expressed predominantly in central nervous system. In humans the picture is somewhat more complicated. NLGN1 and NLGN2 are localized postsynaptically at excitatory and inhibitory synapses respectively and NLGN3 mainly at glia. NLGN3 expression also takes place in other tissues (for example panceras) and NLGN4 mRNA was found in a very broad spectrum of tissues. The interaction between neuroligins 1 and 2 and neurexins initiates synapse formation. By their intracellular interactions with other proteins both neurexins and neuroligins are thought to be perfect candidates for promoting assembly of pre- and postsynaptic protein complexes. What makes this family even more interesting is the fact that mutations in two of the genes (NLGN3 and NLGN4X) are linked to autism. The best studied are rat neuroligins 1 and 2. From the medical point of view the most interesting are NLGN3 and NLGN4X as imbalance between inhibition and excitation in neural circuits have been proposed as one of the mechanisms behind autism.
