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Neuroligins
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.
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IF
YOU WANT TO KNOW MORE... BIBLIOGRAPHY |
| Most recent review about neuroligins:
Dean, C. and Dresbach, T. (2006) Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function Trends Neurosci. 29, 21–29 Ichtchenko, K. et al. (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81, 435–443 rat neuroligins 2 and 3: Ichtchenko, K. et al. (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins. J. Biol. Chem. 271, 2676–2682 human neuroligin 3: Gilbert, M. et al. (2001) Neuroligin 3 is a vertebrate gliotactin expressed in the olfactory ensheathing glia, a growth-promoting class of macroglia. Glia 34, 151–164 human neuroligin 4: Bolliger, M.F. et al. (2001) Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. Biochem. J. 356, 581–588 |
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