Comoletti_2004_J.Neurosci_24_4889

Reference

Title : The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing - Comoletti_2004_J.Neurosci_24_4889
Author(s) : Comoletti D , De Jaco A , Jennings LL , Flynn RE , Gaietta G , Tsigelny I , Ellisman MH , Taylor P
Ref : Journal of Neuroscience , 24 :4889 , 2004
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.
ESTHER : Comoletti_2004_J.Neurosci_24_4889
PubMedSearch : Comoletti_2004_J.Neurosci_24_4889
PubMedID: 15152050

Citations formats

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

Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, Ellisman MH, Taylor P (2004)
Journal of Neuroscience 24 :4889

Array
(
    [id] => 165916
    [paper] => Comoletti_2004_J.Neurosci_24_4889
    [author] => Comoletti D || De Jaco A || Jennings LL || Flynn RE || Gaietta G || Tsigelny I || Ellisman MH || Taylor P
    [year] => 2004
    [title] => The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing
    [journal] => Journal of Neuroscience
    [volume] => 24
    [page] => 4889
    [medline] => 15152050
    [abstract] => Comoletti_2004_J.Neurosci_24_4889
    [kin_reference] => 
    [mutation] => R451C_human-NLGN3 || R471C_ratno-3neur || R473C_ratno-1neur || R473T_ratno-1neur || C286A_ratno-1neur || C286A\/R473C_ratno-1neur
    [kinetic_parameter] => 
    [inhibitor] => 
    [kin_value] => 
    [substrate] => 
    [gene_locus] => Array
        (
        )

    [family] => Neuroligin
    [interact_gene_locus] => 
    [xenobiotic_sensitivity] => 
    [news] => 
    [likid_reference] => 
    [lip_reference] => 
    [gene_locus_frgt] => 
    [structure] => 
    [comment] => 
    [chemical] => 
    [arpigny_jaeger] => 
    [reactivator] => 
    [disease] => 
    [enzyme] => 
    [risk_factor] => 
    [tissue] => 
    [sub_tissue] => 
    [activity] => 
    [specific_activity] => 
    [disease_by_interaction] => 
    [abstract_text] => Array
        (
            [id] => 108790
            [longtext] => Comoletti_2004_J.Neurosci_24_4889
            [content] => 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.
        )

)