Feature Story Research & Innovation
How the upcoming Cryo-EM Core Facility will advance our research
Dr. Jeff Ti
Microtubules are dynamic polymers of α / β -tubulin heterodimers central to cellular processes, such as cell division, cell migration, and organelle transportation. Higher eukaryotes not only have microtubule architectures with diverse structures and functions but also encode substantially expanded α - and β -tubulin gene families (i.e., isotypes). Genetics and cell biology studies suggest that each tubulin gene has a unique cellular function. However, the molecular mechanism by which tubulin isotypes contribute to the regulation of microtubule networks in cells remains poorly understood. I aim to integrate state-of-the-art recombinant protein technology with cryo-electron microscopy (cryo-EM) structural analysis of microtubules to dissect the underlying molecular mechanisms for tubulin isotypes to regulate
microtubule networks. Specifically, I will examine how tubulin isotypes, together with other regulator proteins, control the fundamental biochemical and biophysical properties of microtubules. My previous work has revealed that human β -tubulin isotype compositions can modulate microtubule protofilament number and stability, likely through the isotype-dependent structural plasticity of tubulin subunits (Ti et al., 2018). Here at HKU, using cryo-EM to examine microtubules reconstituted with physiologically relevant tubulin isotype compositions, our findings will contribute to broad research fields, including cancer biology, developmental biology, and neurobiology, where the importance of tubulin isotypes has been demonstrated.
Dr. Jeff Ti’s webpage
Dr. Keda Zhou
state-of-the-art technology, is the most powerful approach to help us determine the structures of transient complexes in the epigenetic regulations. The upcoming new cryo-EM core facility will greatly promote structural studies in both my research group and the whole community. As one of the most advanced cryo-EM facilities in Hong Kong, it offers us the best accessibility and efficiency in screening and data collection. It thus enables us to apply or create new methods to structure determination, and provides teaching and learning opportunities to the students who are enthusiastic about structural biology.
DNA is compacted into chromatin to store the genetic information. As the basic unit of chromatin, the nucleosome is formed by tightly wrapping ~147 bp DNA around a histone octamer, which governs the accessibility of DNA. Nucleosome contains diverse modifications on both DNA and histones. These epigenetic marks not only modulate nucleosome structures and dynamics intrinsically but also recruit various factors to further shape the chromatin. To understand how chromatin factors read, write and erase the epigenetic marks, the most straightforward way is to visualize these processes at the highest resolution. Therefore, single-particle cryo-EM, a
Dr. Keda Zhou’s webpage
Dr. Ruben Hervas Millan
Amyloids are organized cross β -sheet-rich protein aggregates commonly associated with pathological conditions, including Alzheimer’s disease. Our work, starting with the discovery that amyloids could act as a state encoding a “molecular memory”, is changing the view that amyloids are always unregulatable and pathological entities. We have now expanded the list of “functional amyloids” through the identification of additional amyloids involved in determining cell fate and controlling embryonic patterning in the fruit fly. Although our understanding of the principles that govern pathological protein aggregation is increasing, information about how amyloids could be functional, regulatable entities is scarce. This is due, in part, to the lack of high-resolution structural information of functional amyloids isolated from their native environment. In our lab, we use electron cryo-microscopy, which is the only high-resolution structural technique that allows atomic characterization of amyloid
filaments from the native environment, to determine the atomic structure of functional amyloids extracted from their native context and study the relationship between protein aggregation and physiology. We anticipate that studying the structure of endogenous amyloids could offer insight into the functional consequences of amyloid formation in vivo as well as into how organisms regulate amyloid assembly/disassembly to restrict their activity in time and space. In addition, understanding differences between functional and pathological amyloids may inform efforts to combat amyloid in lethal diseases. “Only when the structures of large numbers of proteins have been worked out will biochemists be in a position to answer many of the fundamental questions they have long been asking. —William H. Stein and Stanford Moore”.
Dr. Ruben Hervas Millan’s webpage
Dr. Yang Liu
Nucleosome is the basic structural unit of chromatin, where ~147 bp DNA is wrapped around by histone proteins to regulate the DNA accessibility. The nucleosome structures and dynamics thus regulate all the DNA-related cellular processes such as RNA transcription, DNA replication and DNA repair. Histone chaperones and chromatin remodelers are proteins that function in nucleosome assembly and chromatin architecture regulation, which make DNA accessible to these cellular processes in both normal cells and
cancer/tumor cells. To understand how histone chaperones and chromatin remodelers modulate the nucleosome structure, particularly in cancer/tumor, single-particle cryo-EM for structure determination will be critical to elucidate the interplays of macromolecules and the mechanisms in these essential processes. With the new cryo-EM core facility in HKU, structural biology will be profoundly promoted in the whole community, leading to both research breakthroughs and various collaborations.
Dr. Yang Liu’s webpage
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