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PMID:15152050

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Citation

Comoletti, D, De Jaco, A, Jennings, LL, Flynn, RE, Gaietta, G, Tsigelny, I, Ellisman, MH and Taylor, P (2004) The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J. Neurosci. 24:4889-93

Abstract

The neuroligins are a family of postsynaptic transmembrane proteins that associate with presynaptic partners, the beta-neurexins. Neurexins and neuroligins play a critical role in initiating formation and differentiation of synaptic junctions. A recent study reported that a mutation of neuroligin-3 (NL3), an X-linked gene, was found in siblings with autistic spectrum disorder in which two affected brothers had a point mutation that substituted a Cys for Arg451. To characterize the mutation at the biochemical level, we analyzed expression and activity of the mutated protein. Mass spectrometry comparison of the disulfide bonding pattern between the native and the mutated proteins indicates the absence of aberrant disulfide bonding, suggesting that the secondary structure of the mutated protein is conserved. However, the mutation separately affects protein expression and activity. The Cys mutation causes defective neuroligin trafficking, leading to retention of the protein in the endoplasmic reticulum. This, in turn, decreases the delivery of NL3 to the cell surface. Also, the small fraction of protein that reaches the cell membrane lacks or has markedly diminished beta-neurexin-1 (NX1beta) binding activity. Other substitutions for Arg451 allow for normal cellular expression but diminished affinity for NX1beta. Our findings reveal a cellular phenotype and loss of function for a congenital mutation associated with autistic spectrum disorders.

Links

PubMed Online version:10.1523/JNEUROSCI.0468-04.2004

Keywords

Amino Acid Substitution; Animals; Autistic Disorder/genetics; Cell Adhesion Molecules, Neuronal; Cell Line; Electrophoresis, Polyacrylamide Gel; Fluorescent Antibody Technique; Gene Expression; Humans; Immunoblotting; Mass Spectrometry; Membrane Proteins/chemistry; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mutation; Nerve Tissue Proteins/chemistry; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Protein Binding/genetics; Protein Processing, Post-Translational/genetics; Rats; Recombinant Fusion Proteins/chemistry; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Sequence Deletion; Solubility; Surface Plasmon Resonance; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:NLGN3

enables

GO:0042043: neurexin family protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q63373

F

Seeded From UniProt

complete

RAT:NLGN3

enables

GO:0050839: cell adhesion molecule binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q63373

F

Seeded From UniProt

complete

HUMAN:NLGN3

enables

GO:0050839: cell adhesion molecule binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q62889

F

Seeded From UniProt

complete

HUMAN:NLGN3

enables

GO:0042043: neurexin family protein binding

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:Q62889

F

Seeded From UniProt

complete

RAT:NRX1B

enables

GO:0050839: cell adhesion molecule binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q62889

F

Seeded From UniProt

complete

RAT:NRX1B

enables

GO:0097109: neuroligin family protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q62889

F

Seeded From UniProt

complete

See also

References

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