title: Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.
abstract: Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects--or synaptopathies--are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the Cb(R290H) mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans.
authors: From the Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany, and.
authors: Theofilos
authors: T
authors: Papadopoulos
authors: the Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors: Rudolf
authors: R
authors: Schemm
authors: the Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors: Helmut
authors: H
authors: Grubmüller
authors: From the Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany, and brose@em.mpg.de.
authors: Nils
authors: N
authors: Brose
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004827:Epilepsy / Q000235:genetics*; D056726:Genetic Association Studies; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D021381:Protein Transport; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000737:chemistry
chemical_list: C577410:ARHGEF9 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D064067:Rho Guanine Nucleotide Exchange Factors; C073441:gephyrin; C055525:phosphatidylinositol 3-phosphate; C503256:RHOQ protein, human; D020741:rho GTP-Binding Proteins
keywords: Epilepsy; GABA Receptor; Genetic Disease; Guanine Nucleotide Exchange Factor (GEF); Inhibitory Synapse; Mental Retardation; Synapse