De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A
| Autor: | Tzipora C. Falik-Zaccai, Ehud Banne, Hagay Ladany, Dina Schneidman-Duhovny, Michal Linial, Esther S. Brielle, Limor Kalfon, Danielle Klinger |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Developmental Disabilities Mutant Syntaxin 1 030105 genetics & heredity medicine.disease_cause 03 medical and health sciences Cellular and Molecular Neuroscience Protein structure Munc18 Proteins Exome Sequencing medicine STXBP1 Syntaxin Humans Genetics (clinical) Mutation Brain Diseases Epilepsy Chemistry Brain Munc-18 Electroencephalography Cell biology Psychiatry and Mental health Mutagenesis Insertional 030104 developmental biology Child Preschool Phosphorylation Female SNARE complex |
| Zdroj: | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric GeneticsREFERENCES. 183(7) |
| ISSN: | 1552-485X |
| Popis: | STXBP1, also known as Munc-18, is a master regulator of neurotransmitter release and synaptic function in the human brain through its direct interaction with syntaxin 1A. STXBP1 binds syntaxin 1A is an inactive conformational state. STXBP1 decreases its binding affinity to syntaxin upon phosphorylation, enabling syntaxin 1A to engage in the SNARE complex, leading to neurotransmitter release. STXBP1-related disorders are well characterized by encephalopathy with epilepsy, and a diverse range of neurological and neurodevelopmental conditions. Through exome sequencing of a child with developmental delay, hypotonia, and spasticity, we found a novel de novo insertion mutation of three nucleotides in the STXBP1 coding region, resulting in an additional arginine after position 39 (R39dup). Inconclusive results from state-of-the-art variant prediction tools mandated a structure-based approach using molecular dynamics (MD) simulations of the STXBP1-syntaxin 1A complex. Comparison of the interaction interfaces of the wild-type and the R39dup complexes revealed a reduced interaction surface area in the mutant, leading to destabilization of the protein complex. Moreover, the decrease in affinity toward syntaxin 1A is similar for the phosphorylated STXBP1 and the R39dup. We applied the same MD methodology to seven additional previously reported STXBP1 mutations and reveal that the stability of the STXBP1-syntaxin 1A interface correlates with the reported clinical phenotypes. This study provides a direct link between the outcome of a novel variant in STXBP1 and protein structure and dynamics. The structural change upon mutation drives an alteration in synaptic function. |
| Databáze: | OpenAIRE |
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