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 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 allow therapeutic modulation of mucin
secretory pathways. This data set contains the imaging data for the
studies of primary human airway epithelial cells (HAECs), for the mucin
secretion and airway mucus occlusion studies in mice, and the NAMD input
files and trajectories of the molecular dynamics simulations.