The Laboratory of biological electron microscopy and structural biology

(dr. fei sun’s lab)

 
 

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Research interests

Our research interests are mainly related with the structures and functions of biological macromolecules including membrane proteins and supra macromolecular assemblies. And the aim of our group is to combine various structural research approaches (majorly crystallography and cryo-electron microscopy (cryoEM)) as well as developing new methodologies to determine the architecture of the biological system, in vitro and in vivo, from nano-scale to meso-scale. In the next five years, we will focus on (i) molecular mechanism of mitochondrial and bio-membrane dynamics, (ii) structure and function of supra macromolecular assembly and (iii) methodology development orientating to biological imaging.


  1. 1.Molecular mechanism of mitochondrial and bio-membrane dynamics

Mitochondria are the cell organelles that produce energies (ATP) for cell life. Besides being as an “energy-factory”, the physiological state of mitochondria also regulates the process of cell apoptosis and calcium homeostasis. Therefore, the proper mitochondrial morphology and distribution are tightly connected with the metabolism and survival of cells. Mitochondrial dynamics regulates the morphology and distribution of mitochondria, which includes the fusion and fission of mitochondria, and the motility of mitochondria along the cell cytoskeleton. Our research interests are to understand the structural basis for mitochondrial fusion and fission and how it is regulated, to understand how mitochondria interact with motors and cytoskeletons and how the movement direction of mitochondria is regulated. Mitochondrial fusion and fission process involves the remodeling and phase transition of mitochondrial inner and outer membrane. To understand the common molecular mechanism of bio-membrane remodeling is also of our great interests, which is one key step to disclose the secret of how the cell organelle (e.g. mitochondrion) is formed and kept in specific shape.


2. Structure and function of supra macromolecular complexes

Structural biology has become one of most important tools to understand the principle of the life. Its current frontier is to study the structure and function of important supra macromolecular complex that is composed of many bio-molecules (protein, nucleic acid, sugar, lipid and etc.) and can perform a relative complete function in molecular bioprocess. Most supra macromolecular complexes have large molecular weight, comprises multi-subunits and are highly structural dynamic, which have become a huge barrier to cope with to study their structures and functions. In recent years, with the advantages of direct electron detectors and sophisticated image processing algorithm, three-dimensional reconstruction via cryo-electron microscopy (3DEM) has gone into its evolution phase and become the most important and indispensible approach to study the 3D structures of supra macromolecular complex. Nowadays, there are lots of complicated supra macromolecular complexes whose structures could impossibly be determined by crystallography and NMR approaches and now have been solved in near atomic resolution. In this new era, we will utilize our expertise in the sample preparation of supra macromolecular assembly and in the technology of high-resolution electron cryo-microscopy, to determine the high-resolution 3D structures of several supra macromolecular complexes that are involved in mitochondrial dynamics, bio-membrane remodeling, vesicle trafficking and gene transcription regulation. Based on the high-resolution structural information, we will further their functions in molecular details.


3. Methodology development on the biological imaging

Besides X-ray crystallography and NMR spectrometry, cryoEM has been emerging as one important technology orientating to the current structural biology study. In the past ten years, cryoEM has been developed very fast not only on the hardware but also on the image processing software as well as sample preparation methods. According to different sample characteristics, cryoEM contains three different technologies, which are single particle analysis (SPA), electron tomography (ET) and electron crystallography. Nowadays, there are lots of complicated supra macromolecular complexes whose structures have been solved by SPA in near atomic resolution (3~4 angstrom). However, how to deal with the conformational heterogeneity, how to push the resolution higher to 2 angstrom, how to increase the speed and throughput of structure determination via SPA method, answering those questions will bring another revolution in the field. One of the keys to get the answer is to develop novel image processing algorithm to maximize the information embedded in the original data. We have lots of interests on this direction and will collaborate with other research groups and develop novel image analysis tools based on new mathematics (e.g. Bayesian statistics, compressed sensing and wavelet transformation). The ultimate goal of our work is to realize the structure determination of supra macromolecular complex in atomic resolution (2 angstrom). Besides SPA, we also have lots of interest on ET and have done some work before. We will develop new computational methods to improve the quality of ET and do more work on single particle tomography approach.


Research Achievements (2008-2016)