Data for: Inhibition of Ca2+-triggered secretion by hydrocarbon-stapled peptides

Ca2+-triggered membrane fusion is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion, and other regulated exocytic processes. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex, and sequence conservation and functional studies suggest this mechanism is also conserved for mucin secretion. Disruption of Ca2+-triggered membrane fusion by a pharmacologic agent would have therapeutic value for mucus hypersecretion since it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, COPD and cystic fibrosis. We designed a hydrocarbon-stapled peptide that specifically disrupts Ca2+-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and Ca2+ binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or wit...

钙离子触发的膜融合由一组保守的蛋白协同调控，以介导突触神经递质释放、黏蛋白分泌及其他受调控的胞外分泌过程。就神经递质释放而言，钙离子敏感性由钙离子感受器突触结合蛋白（synaptotagmin）与SNARE复合体（SNARE complex）之间的相互作用赋予；序列保守性与功能研究表明，该机制在黏蛋白分泌过程中同样保守。通过药理学试剂阻断钙离子触发的膜融合，对黏液高分泌症具有治疗价值——因为黏液高分泌是呼吸道病毒感染、哮喘、慢性阻塞性肺疾病（COPD）及囊性纤维化的病理生理过程中气道阻塞的主要诱因。我们设计了一种烃钉合肽（hydrocarbon-stapled peptide），可通过干扰神经元SNARE复合体与突触结合蛋白-1（synaptotagmin-1）的钙离子结合C2B结构域之间的所谓初级相互作用界面，特异性阻断钙离子触发的膜融合。在包含这些神经元突触蛋白的重构系统中，或……