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.
|Original language||American English|
|Number of pages||11|
|Journal||American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics|
|State||Published - 1 Oct 2020|
Bibliographical noteFunding Information:
We gratefully acknowledge the patient families for their contribution in participation in this study. We thank Prof. Shy Arkin from the Hebrew University for providing us with high‐performance computing resources to perform the MD analyses. This study was supported by a fellowship to Danielle Klinger (supported by Yad Hanadiv); HUJI‐CIDR for Michal Linial and Dina Schneidman‐Duhovny; ISF 1466/18 for Dina Schneidman‐Duhovny.
We gratefully acknowledge the patient families for their contribution in participation in this study. We thank Prof. Shy Arkin from the Hebrew University for providing us with high-performance computing resources to perform the MD analyses. This study was supported by a fellowship to Danielle Klinger (supported by Yad Hanadiv); HUJI-CIDR for Michal Linial and Dina Schneidman-Duhovny; ISF 1466/18 for Dina Schneidman-Duhovny.
© 2020 Wiley Periodicals LLC.
- SNARE proteins
- epileptic encephalopathies
- molecular dynamics
- synaptic pathology