Research Topics

Drug Discovery, Enzymology, Genomics, Protein Structure, Protein Synthesis, Protein-Nucleic Acid Interactions, Regulation of Gene Expression, RNA Biology

Disease Research Interests

Cancer, Drug Discovery

B. S. Central China Normal University
Ph.D. Yale University
Postdoctoral Fellow Medical Research Council - Laboratory of Molecular Biology (Cambridge, United Kingdom)

Overview

Protein synthesis and its regulation are essential for gene regulation. For all organisms, protein synthesis takes place in the ribosome, a remarkable molecular machine in all cells. Protein synthesis is mainly regulated at the initiation and the termination stages where the ribosome is complexed with cellular regulatory and translational protein factors to function. Translation directly influences important cellular processes such as development, differentiation, growth, cell fitness and cellular adaptive responses to the external environment.  Consequently, regulatory dysfunction in translation results in numerous diverse human diseases including metabolic disorders, neuronal degenerative diseases and cancer. We are pursuing the molecular understanding of translation and its regulation using biochemical, genomic, and biophysical methods with an emphasis on macromolecule crystallography.

I.  Mechanisms and functions of cap-independent translation in eukaryotic cells

The major pathway for the initiation of protein synthesis in eukaryotes is the cap-dependent pathway,which recruits a set of protein initiation factors to mRNAs that have 5’ m7G caps. However, under certain cellular conditions, such as variations of the cell cycle, developmental patterning, cellular responses to external perturbations and diseases, cells down-regulate cap-dependent translation, and instead, selectively translate subsets of mRNA via an alternative, cap-independent translational pathway. The mRNAs translated in the cap-independent pathway often contain sequence-specific and/or structure-specific regions in their 5’-untranslated regions (5’-UTRs) that recruit translation factors, regulatory proteins and translational machinery in a highly coordinated way. The cap-independent translation is critical to cell’s ability to adapt to the environment and cell survival.

We are investigating the mechanism, function and regulation of cap-independent translation at both genomic and molecular levels.  We are probing the translational status of the cell at a genome-wide scale using high-throughput mRNA-sequencing and ribosome profiling techniques. In parallel, we are using biochemistry, genetics and structural biology to study how translational apparatuses are assembled and what their structures and functions are in the cap-independent translation pathway.

II. Molecular mechanisms of translational termination in bacteria

Ribosomes translate genetic information encoded in messenger RNAs (mRNAs) into proteins in all cells.  It is a large RNA-protein complex with a molecular weight of about 2.5MDa in bacteria.  All ribosomes consist of two asymmetrical subunits that perform different, but closely coupled functions: the small subunit decodes the genetic information in the mRNA;  and the large subunit synthesizes and releases the protein by catalyzing the formation of peptide bonds and the release of nascent proteins from the ribosome.  To ensure the speed and accuracy of protein synthesis, ribosomes orchestrate different scales of conformational rearrangements: from localized conformational changes of specific essential residues to global conformational rearrangements that involve the inter-subunit rotation.

We have identified a new crystal form that can accommodate the bacteria ribosome complexed with translational GTPases, when the two ribosomal subunits rotate relative to each other.  We are using X-ray crystallographic techniques to study ribosomal complexes along the translational pathway with a focus on the translational termination.  A molecular understanding of the bacterial ribosome at the atomic-level detail will provide valuable information for designing antibacterial targets as well as reprogramming translation to probe fundamental questions on the origin and evolution of life.

NIH Ruth L. Kirschstein National Research Service Award 2009-2012