Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis

AUTHORS

Zhou QQiangjun , Lai YYing , Bacaj TTaulant , Zhao MMinglei , Lyubimov AYArtem Y , Uervirojnangkoorn MMonarin , Zeldin OBOliver B , Brewster ASAaron S , Sauter NKNicholas K , Cohen AEAina E , Soltis SMS Michael , Alonso-Mori RRoberto , Chollet MMatthieu , Lemke HTHenrik T , Pfuetzner RARichard A , Choi UBUcheor B , Weis WIWilliam I , Diao JJiajie , Südhof TCThomas C , Brunger ATAxel T . Nature. 2015 8 17; 525(7567). 62-7

PMID: 26280336[PubMed].
PMCID: PMC4607316.

ABSTRACT

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 Ca(2+)- and Mg(2+)-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, Ca(2+)-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca(2+)-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca(2+)-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca(2+) triggering, moves en bloc as Ca(2+) 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.

Tags: 2015