Autism spectrum disorders are among the most devastating disorders of early
childhood in terms of prevalence, family impact, and cost to society. Several
mutations of the coding regions of the neuroligins and neurexins have been
implicated through genetic screens in the pathogenesis of autism and mental
retardation (Jamain et al., 2003; Laumonnier et al., 2004; Yan et al., 2005).
Neurexin and neuroligins are extracellular proteins that associate within the
extracellular synaptic space and appear to be crucial for maintaining the
integrity and functionality of brain circuitry through synaptic transmission
(Varoqueaux et al., 2006). Many neurodevelopmental disorders involve abnormal
synaptic function, the synapses providing the essential connections between
nerve cells that enable signals to be transmitted. As the neuroligins and
neurexins are thus far the only extracellular synaptic proteins clearly
implicated in autism spectrum disorders and mental retardation, determining the
structure of a neuroligin/neurexin complex represents a significant advance toward defining
the molecular organization within the synapse. This structural framework is an
essential foundation for linking genetic information with neuro-developmental
disorders.
Glycosylation of the neuroligins and their unusual extended stalk regions (see
below) have rendered a crystallographic solution of the structure of the
extracellular portion of a neuroligin, as well as a neuroligin- neurexin
complex, a challenging endeavor. We therefore turned to small angle X-ray and
neutron solution scattering to determine the molecular shapes of neuroligin and
neurexin, and their dispositions in their complex, in order to enhance our
understanding of the complex formation within the synaptic space environment.
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Figure 1 - Ribbon representation of the neuroligin-1/b-neurexin Complex. View from
the pre-synapse - Green, neuroligin dimer; red, neurexin molecules. Residues
found to be mutated in autism are shown as yellow amino acid side chains.
N-linked glycosylation sites in neuroligin are also shown in red, position of
alternative splicing are shown in cyan.
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Using small-angle X-ray scattering data from Beam Line 4.2 at SSRL, in
combination with homology modeling, we first determined a three-dimensional
structural model of the dimeric acetylcholinesterase-like domain for
neuroligin-1. We then showed that all four neuroligin isoforms have similar
overall shapes and dimensions as evidenced by their distance distribution
functions, radius of gyration, maximum dimension, and three-dimensional shape
reconstructions. The solution scattering data further indicate that the stalk
region connecting the globular domain of the neuroligins with their
transmembrane domain is elongated and projects away from the globular domain.
Using the newly determined neuroligin-1 structure, and complementing our X-ray
data with neutron contrast variation data from a complex of neuroligin-1 and a
deuterated neurexin, we were able to determine the first three dimensional
structural model of neuroligin-1 complexed with
b-neurexin (Figure 1).
The combination of X-ray scattering with neutron contrast variation, sequence
analysis, modeling, biochemical and mutagenesis data has allowed us to put
forward a model of the neurexin and neuroligin complex in the synaptic space
(Figure 2). This model provides an important structural framework for linking
genetic information on mutated neurexins and neuroligins with
neuro-developmental disorders.
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Figure 2 - Model of the neuroligin-1/b-neurexin assembly in the nerve
synapse. The neurexin/neuroligin complex is tethered to the pre- and
post-synaptic membranes through their respective O-linked glycosylated regions
that have been drawn extended to position the complex in the synaptic space.
Arrows specify the approximate sizes of the synaptic cleft and the
complex. |
Primary Citation
Comoletti D, Grishaev A, Whitten AE, Tsigelny I, Taylor P, Trewhella J. (2007)
Synaptic arrangement of the neuroligin/beta-neurexin complex revealed by X-ray
and neutron scattering. Structure. 15:693-705.
References
Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I.C.,
Soderstrom, H., Giros, B., Leboyer, M., Gillberg, C., Bourgeron, T. Paris
Autism Research International Sibpair Study. (2003) Mutations of the X-linked
genes encoding neuroligins NLGN3 and NLGN4 are associated with autism, Nat
Genet. 34, 27-29.
Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP,
Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP,
Ropers HH, Hamel BC, Andres C, Barthelemy C, Moraine C, Briault S. (2004)
X-linked mental retardation and autism are associated with a mutation in the
NLGN4 gene, a member of the neuroligin family. Am J Hum Genet. 74:552-7.
Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M, Gottmann K, Zhang W,
Sudhof TC, Brose N. (2006) Neuroligins determine synapse maturation and
function. Neuron. 51:741-54.
Yan, J., Oliveira, G., Coutinho, A., Yang, C., Feng, J., Katz, C., Sram, J.,
Bockholt, A., Jones, I.R., Craddock, N., Cook, E.H., Vicente, A., Sommer, S.S.
(2005) Analysis of the neuroligin 3 and 4 genes in autism and other
neuropsychiatric patients, Mol Psychiatry 10, 329-332.
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| SSRL is supported
by the Department of Energy, Office of Basic Energy Sciences. The SSRL
Structural Molecular Biology Program is supported by the Department of Energy,
Office of Biological and Environmental Research, and by the National Institutes
of Health, National Center for Research Resources, Biomedical Technology
Program, and the National Institute of General Medical Sciences. |
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