The complexin C-terminal amphipathic helix stabilizes the fusion pore open state by sculpting membranes

Autor: Kevin C. Courtney, Lanxi Wu, Taraknath Mandal, Mark Swift, Zhao Zhang, Mohammad Alaghemandi, Zhenyong Wu, Mazdak M. Bradberry, Claire Deo, Luke D. Lavis, Niels Volkmann, Dorit Hanein, Qiang Cui, Huan Bao, Edwin R. Chapman
Přispěvatelé: University of Wisconsin-Madison, Boston University [Boston] (BU), Indian Institute of Technology Kanpur (IIT Kanpur), The Scintillon Institute, Howard Hughes Medical Institute (HHMI), European Molecular Biology Laboratory [Heidelberg] (EMBL), Imagerie structurale - Structural Image Analysis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Études structurales de machines moléculaires in cellulo - Structural studies of macromolecular machines in cellula, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), The Scripps Research Institute [La Jolla, San Diego], This work was supported by Pew Charitable Trust grant no. 864K625 (E.R.C. and D.H.), National Institutes of Health grant nos. MH061876 and NS097362 (E.R.C.), P01-GM121203 (N.V.) and DP2GM140920 (H.B.). Equipment for the cryo-CLEM and in situ cellular tomography workflow used in this work was funded by National Institutes of Health grant nos. S10-OD012372 (D.H.), S10-OD026926 (D.H.), P01-GM121203 (N.V.) and R01-AI132378 (N.V., D.H.), and Pew Charitable Trust grant no. 864K625. The computational component is supported by the grant no. NSF-DMS1661900 (Q.C.) Computational resources from the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF grant no. OCI-1053575 (Q.C.), are greatly appreciated, computations are also supported in part by the Shared Computing Cluster, which is administered by Boston University’s Research Computing Services. E.R.C. is an Investigator of the Howard Hughes Medical Institute.
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Nature Structural and Molecular Biology
Nature Structural and Molecular Biology, 2022, 29 (2), pp.97-107. ⟨10.1038/s41594-021-00716-0⟩
Nat Struct Mol Biol
ISSN: 1545-9993
1545-9985
DOI: 10.1038/s41594-021-00716-0⟩
Popis: International audience; Neurotransmitter release is mediated by proteins that drive synaptic vesicle fusion with the presynaptic plasma membrane. While soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) form the core of the fusion apparatus, additional proteins play key roles in the fusion pathway. Here, we report that the C-terminal amphipathic helix of the mammalian accessory protein, complexin (Cpx), exerts profound effects on membranes, including the formation of pores and the efficient budding and fission of vesicles. Using nanodisc-black lipid membrane electrophysiology, we demonstrate that the membrane remodeling activity of Cpx modulates the structure and stability of recombinant exocytic fusion pores. Cpx had particularly strong effects on pores formed by small numbers of SNAREs. Under these conditions, Cpx increased the current through individual pores 3.5-fold, and increased the open time fraction from roughly 0.1 to 1.0. We propose that the membrane sculpting activity of Cpx contributes to the phospholipid rearrangements that underlie fusion by stabilizing highly curved membrane fusion intermediates.
Databáze: OpenAIRE
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