title: Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.
abstract: Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phospho-mimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.
authors: Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; Department of Biology, The Johns Hopkins University, Baltimore, MD 21218;
authors: Michael A
authors: MA
authors: Bemben
authors: Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, CA 94158;
authors: Quynh-Anh
authors: QA
authors: Nguyen
authors: Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; and.
authors: Tongguang
authors: T
authors: Wang
authors: Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors: Yan
authors: Y
authors: Li
authors: Departments of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco, CA 94158; nicoll@cmp.ucsf.edu rochek@ninds.nih.gov.
authors: Roger A
authors: RA
authors: Nicoll
authors: Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; nicoll@cmp.ucsf.edu rochek@ninds.nih.gov.
authors: Katherine W
authors: KW
authors: Roche
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D050505:Mutant Proteins; C430845:NLGN4X protein, human; D010769:Phosphothreonine; D011493:Protein Kinase C
keywords: autism; development; neuroligin; synaptic adhesion molecule; synaptogenesis