详情页 - 四川省肿瘤医院知识库

当前位置：首页 > 详情页

Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides.

文献详情

资源类型：

Pubmed体系：

收录情况： ◇ 自然指数

作者：

机构： [1]Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA [2]Institute of General Physiology, Ulm University, Ulm, Germany [3]Department of Pulmonary Medicine,University of Texas MD Anderson Cancer Center, Houston, TX, USA [4]Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA [5]Institute for Applied Cancer Science, Universityof Texas MD Anderson Cancer Center, Houston, TX, USA [6]Present address: National Clinical Research Center for Geriatrics, West China Hospital, State Key Laboratory of Biotherapy andCollaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China [7]Department of Cell & Developmental Biology, Vanderbilt Brain Institute, Center forStructural Biology, Vanderbilt University, TN, USA [8]Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA [9]Department of Chemistry, Fudan University, Shanghai, China

出处：

DOI：

ISSN：

摘要：

Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1-4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7-11. Here 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 the Ca2+-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca2+-triggered fusion at physiological Ca2+ concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca2+-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.© 2022. The Author(s).

语种：

PubmedID：

中科院(CAS)分区：

出版当年[2022]版：

大类 | 1 区

综合性期刊

小类 | 1 区综合性期刊

最新[2023]版：

大类 | 1 区

综合性期刊

小类 | 1 区综合性期刊

第一作者：

第一作者机构： [1]Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA [6]Present address: National Clinical Research Center for Geriatrics, West China Hospital, State Key Laboratory of Biotherapy andCollaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

通讯作者：

通讯机构： [1]Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA [4]Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA [6]Present address: National Clinical Research Center for Geriatrics, West China Hospital, State Key Laboratory of Biotherapy andCollaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

推荐引用方式(GB/T 7714)：

APA：

MLA：