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De novo STXBP1 mutation in a child with developmental delay and spasticity reveals a major structural alteration in the interface with syntaxin 1A.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics ( IF 2.8 ) Pub Date : 2020-08-19 , DOI: 10.1002/ajmg.b.32816
Ehud Banne 1 , Tzipora Falik-Zaccai 2, 3 , Esther Brielle 4, 5 , Limor Kalfon 2 , Hagay Ladany 2 , Danielle Klinger 4 , Dina Schneidman-Duhovny 4, 6 , Michal Linial 4
Affiliation  

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.

中文翻译:

患有发育延迟和痉挛的儿童的从头STXBP1突变表明与syntaxin 1A的界面发生了重大结构变化。

STXBP1,也称为Munc-18,通过与语法1A的直接相互作用,是人脑中神经递质释放和突触功能的主要调节剂。STXBP1绑定语法in 1A是无效构象状态。STXBP1在磷酸化后降低了其与语法素的结合亲和力,使语法素1A能够与SNARE复合体结合,从而导致神经递质释放。STXBP1相关疾病的特征是患有癫痫病的脑病,以及各种神经系统疾病和神经发育疾病。通过对发育发育迟缓,肌张力低下和痉挛的儿童进行外显子组测序,我们在STXBP1编码区域发现了三个核苷酸的新的从头插入突变,从而在位置39(R39dup)之后产生了另一个精氨酸。最新的变体预测工具的不确定性结果要求使用STXBP1–Syntaxin 1A复合物的分子动力学(MD)模拟来基于结构的方法。比较野生型和R39dup复合物的相互作用界面,发现突变体中相互作用表面积减少,从而导致蛋白质复合物不稳定。此外,对于磷酸化的STXBP1和R39dup,对语法1A的亲和力降低相似。我们将相同的MD方法应用于另外七个先前报道的STXBP1突变,并揭示了STXBP1-syntaxin 1A接口的稳定性与已报道的临床表型相关。这项研究提供了STXBP1中新变体的结果与蛋白质结构和动力学之间的直接联系。
更新日期:2020-09-11
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