Qiangjun Zhou received his Ph.D. in Molecular Biology and Biochemistry from the Institute of Biophysics, Chinese Academy of Science in 2012. Currently, he is a postdoctoral fellow with Drs. Axel T. Brunger and Thomas C. Südhof in the Department of Molecular and Cellular Physiology.

Honors & Awards

  • K99 Pathway to Independence Award, National Institute of Mental Health (2017-)


All Publications

  • The pre-synaptic fusion machinery. Current opinion in structural biology Brunger, A. T., Choi, U. B., Lai, Y., Leitz, J., White, K. I., Zhou, Q. 2019; 54: 179–88


    Here, we review recent insights into the neuronal presynaptic fusion machinery that releases neurotransmitter molecules into the synaptic cleft upon stimulation. The structure of the pre-fusion state of the SNARE/complexin-1/synaptotagmin-1 synaptic protein complex suggests a new model for the initiation of fast Ca2+-triggered membrane fusion. Functional studies have revealed roles of the essential factors Munc18 and Munc13, demonstrating that a part of their function involves the proper assembly of synaptic protein complexes. Near-atomic resolution structures of the NSF/alphaSNAP/SNARE complex provide first glimpses of the molecular machinery that disassembles the SNARE complex during the synaptic vesicle cycle. These structures show how this machinery captures the SNARE substrate and provide clues as to a possible processing mechanism.

    View details for PubMedID 30986753

  • Resolving indexing ambiguities in X-ray free-electron laser diffraction patterns. Acta crystallographica. Section D, Structural biology Uervirojnangkoorn, M., Lyubimov, A. Y., Zhou, Q., Weis, W. I., Brunger, A. T. 2019; 75 (Pt 2): 234–41


    Processing X-ray free-electron laser (XFEL) diffraction images poses challenges, as an XFEL pulse is powerful enough to destroy or damage the diffracting volume and thereby yields only one diffraction image per volume. Moreover, the crystal is stationary during the femtosecond pulse, so reflections are generally only partially recorded. Therefore, each XFEL diffraction image must be scaled individually and, ideally, corrected for partiality prior to merging. An additional complication may arise owing to indexing ambiguities when the symmetry of the Bravais lattice is higher than that of the space group, or when the unit-cell dimensions are similar to each other. Here, an automated method is presented that diagnoses these indexing ambiguities based on the Brehm-Diederichs algorithm [Brehm & Diederichs (2014), Acta Cryst. D70, 101-109] and produces a consistent indexing choice for the large majority of diffraction images. This method was applied to an XFEL diffraction data set measured from crystals of the neuronal SNARE-complexin-1-synaptotagmin-1 complex. After correcting the indexing ambiguities, substantial improvements were observed in the merging statistics and the atomic model refinement R values. This method should be a useful addition to the arsenal of tools for the processing of XFEL diffraction data sets.

    View details for PubMedID 30821711

  • NSF-mediated disassembly of on and off-pathway SNARE complexes and inhibition by complexin. eLife Choi, U. B., Zhao, M., White, K. I., Pfuetzner, R. A., Esquivies, L., Zhou, Q., Brunger, A. T. 2018; 7


    SNARE complex disassembly by the ATPase NSF is essential for neurotransmitter release and other membrane trafficking processes. We developed a single molecule FRET assay to monitor repeated rounds of NSF-mediated disassembly and reassembly of individual SNARE complexes. For ternary neuronal SNARE complexes, disassembly proceeds in a single step within 100 msec. We observed short- (< 0.32 sec) and long-lived ({greater than or equal to} 0.32 sec) disassembled states. The long-lived states represent fully disassembled SNARE complex, while the short-lived states correspond to failed disassembly or immediate re-assembly. Either high ionic strength or decreased alphaSNAP concentration reduces the disassembly rate while increasing the frequency of short-lived states. NSF is also capable of disassembling anti-parallel ternary SNARE complexes, suggesting a role in quality control. Finally, complexin-1 competes with alphaSNAP binding to the SNARE complex; addition of complexin-1 has an effect similar to that of decreasing the alphaSNAP concentration, suggesting a possible regulatory role in disassembly.

    View details for PubMedID 29985126

  • Ca2+-Triggered Synaptic Vesicle Fusion Initiated by Release of Inhibition. Trends in cell biology Brunger, A. T., Leitz, J., Zhou, Q., Choi, U. B., Lai, Y. 2018


    Recent structural and functional studies of the synaptic vesicle fusion machinery suggest an inhibited tripartite complex consisting of neuronal soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), synaptotagmin, and complexin prior to Ca2+-triggered synaptic vesicle fusion. We speculate that Ca2+-triggered fusion commences with the release of inhibition by Ca2+ binding to synaptotagmin C2 domains. Subsequently, fusion is assisted by SNARE complex zippering and by active membrane remodeling properties of synaptotagmin. This additional, inhibitory role of synaptotagmin may be a general principle since other recent studies suggest that Ca2+ binding to extended synaptotagmin C2 domains enables lipid transport by releasing an inhibited state of the system, and that Munc13 may nominally be in an inhibited state, which is released upon Ca2+ binding to one of its C2 domains.

    View details for PubMedID 29706534

  • Molecular Mechanisms of Fast Neurotransmitter Release ANNUAL REVIEW OF BIOPHYSICS, VOL 47 Brunger, A. T., Choi, U. B., Lai, Y., Leitz, J., Zhou, Q., Dill, K. A. 2018; 47: 469–97


    This review summarizes current knowledge of synaptic proteins that are central to synaptic vesicle fusion in presynaptic active zones, including SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptors), synaptotagmin, complexin, Munc18 (mammalian uncoordinated-18), and Munc13 (mammalian uncoordinated-13), and highlights recent insights in the cooperation of these proteins for neurotransmitter release. Structural and functional studies of the synaptic fusion machinery suggest new molecular models of synaptic vesicle priming and Ca2+-triggered fusion. These studies will be a stepping-stone toward answering the question of how the synaptic vesicle fusion machinery achieves such high speed and sensitivity.

    View details for PubMedID 29792815

  • The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature Zhou, Q., Zhou, P., Wang, A. L., Wu, D., Zhao, M., Südhof, T. C., Brunger, A. T. 2017; 548 (7668): 420–25


    Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE-complexin-synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface. Mutations that disrupt either interface in solution also severely impair evoked synchronous release in neurons, suggesting that both interfaces are essential for the primed pre-fusion state. Ca(2+) binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. The tripartite SNARE-complexin-synaptotagmin-1 complex at a synaptic vesicle docking site has to be unlocked for triggered fusion to start, explaining the cooperation between complexin and synaptotagmin-1 in synchronizing evoked release on the sub-millisecond timescale.

    View details for PubMedID 28813412

  • Advances in X-ray free electron laser (XFEL) diffraction data processing applied to the crystal structure of the synaptotagmin-1 / SNARE complex. eLife Lyubimov, A. Y., Uervirojnangkoorn, M., Zeldin, O. B., Zhou, Q., Zhao, M., Brewster, A. S., Michels-Clark, T., Holton, J. M., Sauter, N. K., Weis, W. I., Brunger, A. T. 2016; 5


    X-ray free electron lasers (XFELs) reduce the effects of radiation damage on macromolecular diffraction data and thereby extend the limiting resolution. Previously, we adapted classical post-refinement techniques to XFEL diffraction data to produce accurate diffraction data sets from a limited number of diffraction images (Uervirojnangkoorn et al., 2015), and went on to use these techniques to obtain a complete data set from crystals of the synaptotagmin-1 / SNARE complex and to determine the structure at 3.5 Å resolution (Zhou et al., 2015). Here, we describe new advances in our methods and present a reprocessed XFEL data set of the synaptotagmin-1 / SNARE complex. The reprocessing produced small improvements in electron density maps and the refined atomic model. The maps also contained more information than those of a lower resolution (4.1 Å) synchrotron data set. Processing a set of simulated XFEL diffraction images revealed that our methods yield accurate data and atomic models.

    View details for DOI 10.7554/eLife.18740

    View details for PubMedID 27731796

    View details for PubMedCentralID PMC5094853

  • Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis. Nature Zhou, Q., Lai, Y., Bacaj, T., Zhao, M., Lyubimov, A. Y., Uervirojnangkoorn, M., Zeldin, O. B., Brewster, A. S., Sauter, N. K., Cohen, A. E., Soltis, S. M., Alonso-Mori, R., Chollet, M., Lemke, H. T., Pfuetzner, R. A., Choi, U. B., Weis, W. I., Diao, J., Südhof, T. C., Brunger, A. T. 2015; 525 (7567): 62-67


    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.

    View details for DOI 10.1038/nature14975

    View details for PubMedID 26280336

  • ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature Diao, J., Liu, R., Rong, Y., Zhao, M., Zhang, J., Lai, Y., Zhou, Q., Wilz, L. M., Li, J., Vivona, S., Pfuetzner, R. A., Brunger, A. T., Zhong, Q. 2015; 520 (7548): 563-566


    Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation. Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes. However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as beclin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex, promotes membrane tethering of protein-free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8). ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain, and stabilizes the STX17-SNAP29 binary t-SNARE complex on autophagosomes. The STX17 binding, membrane tethering and fusion-enhancing activities of ATG14 require its homo-oligomerization by cysteine repeats. In ATG14 homo-oligomerization-defective cells, autophagosomes still efficiently form but their fusion with endolysosomes is blocked. Recombinant ATG14 homo-oligomerization mutants also completely lose their ability to promote membrane tethering and to enhance SNARE-mediated fusion in vitro. Taken together, our data suggest an autophagy-specific membrane fusion mechanism in which oligomeric ATG14 directly binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion.

    View details for DOI 10.1038/nature14147

    View details for PubMedID 25686604

  • Mechanistic insights into the recycling machine of the SNARE complex. Nature Zhao, M., Wu, S., Zhou, Q., Vivona, S., Cipriano, D. J., Cheng, Y., Brunger, A. T. 2015; 518 (7537): 61-67


    Evolutionarily conserved SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors) proteins form a complex that drives membrane fusion in eukaryotes. The ATPase NSF (N-ethylmaleimide sensitive factor), together with SNAPs (soluble NSF attachment protein), disassembles the SNARE complex into its protein components, making individual SNAREs available for subsequent rounds of fusion. Here we report structures of ATP- and ADP-bound NSF, and the NSF/SNAP/SNARE (20S) supercomplex determined by single-particle electron cryomicroscopy at near-atomic to sub-nanometre resolution without imposing symmetry. Large, potentially force-generating, conformational differences exist between ATP- and ADP-bound NSF. The 20S supercomplex exhibits broken symmetry, transitioning from six-fold symmetry of the NSF ATPase domains to pseudo four-fold symmetry of the SNARE complex. SNAPs interact with the SNARE complex with an opposite structural twist, suggesting an unwinding mechanism. The interfaces between NSF, SNAPs, and SNAREs exhibit characteristic electrostatic patterns, suggesting how one NSF/SNAP species can act on many different SNARE complexes.

    View details for DOI 10.1038/nature14148

    View details for PubMedID 25581794

    View details for PubMedCentralID PMC4320033

  • Data Exploration Toolkit for serial diffraction experiments. Acta crystallographica. Section D, Biological crystallography Zeldin, O. B., Brewster, A. S., Hattne, J., Uervirojnangkoorn, M., Lyubimov, A. Y., Zhou, Q., Zhao, M., Weis, W. I., Sauter, N. K., Brunger, A. T. 2015; 71: 352-356


    Ultrafast diffraction at X-ray free-electron lasers (XFELs) has the potential to yield new insights into important biological systems that produce radiation-sensitive crystals. An unavoidable feature of the `diffraction before destruction' nature of these experiments is that images are obtained from many distinct crystals and/or different regions of the same crystal. Combined with other sources of XFEL shot-to-shot variation, this introduces significant heterogeneity into the diffraction data, complicating processing and interpretation. To enable researchers to get the most from their collected data, a toolkit is presented that provides insights into the quality of, and the variation present in, serial crystallography data sets. These tools operate on the unmerged, partial intensity integration results from many individual crystals, and can be used on two levels: firstly to guide the experimental strategy during data collection, and secondly to help users make informed choices during data processing.

    View details for DOI 10.1107/S1399004714025875

    View details for PubMedID 25664746

    View details for PubMedCentralID PMC4321488

  • Molecular insights into the membrane-associated phosphatidylinositol 4-kinase II alpha NATURE COMMUNICATIONS Zhou, Q., Li, J., Yu, H., Zhai, Y., Gao, Z., Liu, Y., Pang, X., Zhang, L., Schulten, K., Sun, F., Chen, C. 2014; 5


    Phosphatidylinositol 4-kinase IIα (PI4KIIα), a membrane-associated PI kinase, plays a central role in cell signalling and trafficking. Its kinase activity critically depends on palmitoylation of its cysteine-rich motif (-CCPCC-) and is modulated by the membrane environment. Lack of atomic structure impairs our understanding of the mechanism regulating kinase activity. Here we present the crystal structure of human PI4KIIα in ADP-bound form. The structure identifies the nucleotide-binding pocket that differs notably from that found in PI3Ks. Two structural insertions, a palmitoylation insertion and an RK-rich insertion, endow PI4KIIα with the 'integral' membrane-binding feature. Molecular dynamics simulations, biochemical and mutagenesis studies reveal that the palmitoylation insertion, containing an amphipathic helix, contributes to the PI-binding pocket and anchors PI4KIIα to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KIIα's activity. We conclude from our results that PI4KIIα's activity is regulated indirectly through changes in the membrane environment.

    View details for DOI 10.1038/ncomms4552

    View details for Web of Science ID 000334304400001

    View details for PubMedID 24675427

    View details for PubMedCentralID PMC3974213

  • Revealing various coupling of electron transfer and proton pumping in mitochondrial respiratory chain CURRENT OPINION IN STRUCTURAL BIOLOGY Sun, F., Zhou, Q., Pang, X., Xu, Y., Rao, Z. 2013; 23 (4): 526-538


    Cellular respiration is the process that releases energy from food and supplies energy for life processes. The mitochondrial respiratory chain is the final and most important step for cellular respiration and is located on the inner membrane of mitochondrion and comprises four large trans-membrane protein complexes (respiratory chain Complexes I, II, III and IV) as well as ubiquinone between Complexes I/II and III and cytochrome c between Complexes III and IV. The function of mitochondrial respiratory chain is biological oxidation by transferring electrons from NADH and succinate to oxygen and then generating proton gradient across the inner membrane. Such proton gradient is utilized by ATP synthase (ATPase, also called as Complex V) to produce energy molecules ATP. Structural studies of mitochondrial respiratory membrane protein complexes are important to understand the mechanism of electron transfer and the redox-coupled proton translocation across the inner membrane. Here, according to the time line, we reviewed the great achievements on structural studies of mitochondrial respiratory complexes in the past twenty years as well as the recent research progresses on the structures of mitochondrial respiratory supra-complexes.

    View details for DOI 10.1016/

    View details for Web of Science ID 000323590500007

    View details for PubMedID 23867107

  • Thiabendazole inhibits ubiquinone reduction activity of mitochondrial respiratory complex II via a water molecule mediated binding feature PROTEIN & CELL Zhou, Q., Zhai, Y., Lou, J., Liu, M., Pang, X., Sun, F. 2011; 2 (7): 531-542


    The mitochondrial respiratory complex II or succinate: ubiquinone oxidoreductase (SQR) is a key membrane complex in both the tricarboxylic acid cycle and aerobic respiration. Five disinfectant compounds were investigated with their potent inhibition effects on the ubiquinone reduction activity of the porcine mitochondrial SQR by enzymatic assay and crystallography. Crystal structure of the SQR bound with thiabendazole (TBZ) reveals a different inhibitor-binding feature at the ubiquinone binding site where a water molecule plays an important role. The obvious inhibitory effect of TBZ based on the biochemical data (IC(50) ~100 μmol/L) and the significant structure-based binding affinity calculation (~94 μmol/L) draw the suspicion of using TBZ as a good disinfectant compound for nematode infections treatment and fruit storage.

    View details for DOI 10.1007/s13238-011-1079-1

    View details for Web of Science ID 000310521800004

    View details for PubMedID 21822798

    View details for PubMedCentralID PMC4875242