Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis

Zhou, Qiangjun; Lai, Ying; Bacaj, Taulant; Zhao, Minglei; Lyubimov, Artem Y.; Uervirojnangkoorn, Monarin; Zeldin, Oliver B.; Brewster, Aaron S.; Sauter, Nicholas K.; Cohen, Aina E.; Soltis, S. Michael; Alonso-Mori, Roberto; Chollet, Matthieu; Lemke, Henrik T.; Pfuetzner, Richard A.; Choi, Ucheor B.; Weis, William I.; Diao, Jiajie; Südhof, Thomas C.; Brunger, Axel T.

doi:10.1038/nature14975

Title: Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis

Journal Article · Mon Aug 17 00:00:00 EDT 2015 · Nature (London)

DOI:https://doi.org/10.1038/nature14975· OSTI ID:1221448

Zhou, Qiangjun ^[1]; Lai, Ying ^[1]; Bacaj, Taulant ^[2]; Zhao, Minglei ^[1]; Lyubimov, Artem Y. ^[1]; Uervirojnangkoorn, Monarin ^[1]; Zeldin, Oliver B. ^[1]; Brewster, Aaron S. ^[3]; Sauter, Nicholas K. ^[3]; Cohen, Aina E. ^[4]; Soltis, S. Michael ^[4]; Alonso-Mori, Roberto ^[4]; Chollet, Matthieu ^[4]; Lemke, Henrik T. ^[4]; Pfuetzner, Richard A. ^[1]; Choi, Ucheor B. ^[1]; Weis, William I. ^[5]; Diao, Jiajie ^[1]; Südhof, Thomas C. ^[2]; Brunger, Axel T. ^[1]

Stanford Univ., CA (United States). Howard Hughes Medical Institute; Stanford Univ., CA (United States). Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology
Stanford Univ., CA (United States). Howard Hughes Medical Institute
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
SLAC National Accelerator Lab., Stanford, CA (United States)
Stanford Univ., CA (United States). Departments of Structural Biology, Molecular and Cellular Physiology, and Photon Science

Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca2+-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca2+-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca2+-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca2+triggering, moves en bloc as Ca2+influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Contributing Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515; P41GM103393; AC02-05CH11231

OSTI ID:: 1221448

Alternate ID(s):: OSTI ID: 1512250

Journal Information:: Nature (London), Vol. 525, Issue 7567; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 201 works

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