Welcome to the Zhou Lab!
Cell-to-cell communication is essential for the development and function of multicellular organisms. We focus on two types of intercellular communication: synaptic transmission and exosome-based cell-to-cell communication. Similar to other biological activities, they are highly complex and tightly regulated processes by a large number of proteins. The function of almost all proteins is dependent on their higher-order assembly into nanoscale molecular machines with its biological membrane. However, defining molecular assembly, spatial organization and dynamics of these nanoscale molecular machines is a daunting task largely because of the technical challenges imposed by the cellular and molecular complexity.
Cryogenic electron tomography (cryo-ET) can provide 3D images (tomograms) of nanoscale molecular machines or cellular landscapes in their near-native states. Subtomogram averaging and classification allow any repetitive structures to be averaged to improve and achieve close-to-nanometer resolution or better (3-20 Å). Moreover, cryogenic focused ion beam (cryo-FIB) milling has been developed to create a 150-250 nm thick cell lamella for overcoming the limitation of sample thickness for cryo-ET imaging of large eukaryotic cells in situ. To target areas of interest in the cell, cryogenic correlative light and electron microscopy (cryo-CLEM) has become a powerful and broadly available tool owing to the combined advantages of both imaging techniques. We combine these techniques to bridge the gap and link high resolution (sub-3 Å) structural information with physiological functions at the molecular and cellular levels.
- In situ molecular architecture and nanoscale organization of synaptic protein super-complexes
Different modes of synaptic transmission play distinct roles in encoding and transmitting information in brain circuits, which is essential for perception, decision making, learning and memory formation. However, it remains unclear how these modes of synaptic transmission regulate neural circuit activity and how the molecular mechanisms differ between these modes. Synapses constitute the most complex cell-cell junctions in the body with more than 2,000 different synaptic proteins. Especially, the presynaptic active zone, the postsynaptic density (PSD) and the synaptic cleft are membrane-protein specializations, each containing protein complexes unique to their function. Recent studies also revealed that supramolecular assembly is likely to be a general property of synaptic proteins, but defining the assembly and nanoscale organization of these synaptic protein super-complexes remains elusive.
- Molecular mechanism and regulation of exosome secretion in cancer and central nervous system
Nano-sized vesicles called “exosomes” which contain genetic material, proteins and lipids are released upon exocytic fusion of multivesicular bodies (MVBs) with the plasma membrane (PM). They are found to be particularly involved in various stages of tumor and cell-to-cell communication in the brain. However, the molecular mechanisms and regulation of exosome secretion are poorly understood.
A broad long-term goal is to apply knowledge gained from above mechanistic studies to investigate how dysfunction in certain aspects of neurotransmitter release and neuronal development contributes to brain disorders.