
Journal
- MedComm Introduction
- Molecular Biomedicine Introduction
- Signal Transduction and Targeted Therapy Introduction
- MedComm | The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19
- MedComm | Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu-opioid receptor
Editors-in-Chief:
Carlo M.Croce
Prof. Kang Zhang
Yu-quan Wei

Editors-in-Chief:
James H.Naisimth
Günter P. Wagner
Yu-quan Wei

Editors-in-Chief:
Arnold J.M.Driessen
Yu-quan Wei

Editors-in-Chief:
Robin Ali
Michael Karin
Kang Zhang

Editors-in-Chief:
Mohan Edirisinghe
Zhiyong Qian

Editors-in-Chief:
Guido Kroemer
Yong Peng

Journal
- MedComm Introduction
- Molecular Biomedicine Introduction
- Signal Transduction and Targeted Therapy Introduction
- MedComm | The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19
- MedComm | Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu-opioid receptor
Editors-in-Chief:
Carlo M.Croce
Prof. Kang Zhang
Yu-quan Wei

Editors-in-Chief:
James H.Naisimth
Günter P. Wagner
Yu-quan Wei

Editors-in-Chief:
Arnold J.M.Driessen
Yu-quan Wei

Editors-in-Chief:
Robin Ali
Michael Karin
Kang Zhang

Editors-in-Chief:
Mohan Edirisinghe
Zhiyong Qian

Editors-in-Chief:
Guido Kroemer
Yong Peng

Membrane fusion triggered by Ca2+ 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 that this mechanism is also conserved for mucin secretion. 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 fibrosis. Here authors 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.
2022-03-23

Nature

West China Hospital, Sichuan University
Lipoproteins in the outer membrane of Gram-negative bacteria are involved in various vital physiological activities, including multidrug resistance. Synthesized in the cytoplasm and matured in the inner membrane, lipoproteins must be transported to the outer membrane through the Lol pathway mediated by the ATP-binding cassette transporter LolCDE in the inner membrane via an unknown mechanism. Here, we report cryo-EM structures of Escherichia coli LolCDE in apo, lipoprotein-bound, LolA-bound, ADP-bound and AMP-PNP-bound states at a resolution of 3.2–3.8 Å, covering the complete lipoprotein transport cycle. Mutagenesis and in vivo viability assays verify features of the structures and reveal functional residues and structural characteristics of LolCDE. The results provide insights into the mechanisms of sorting and transport of outer-membrane lipoproteins and may guide the development of novel therapies against multidrug-resistant Gram-negative bacteria.
2021-03-29

Nat Struct Mol Biol

West China Hospital, SCU