The laboratory of Dr. Zhang studies structural and functional relations of macromolecules, which play crucial roles in variety of biological processes. The following are several areas that we are currently focusing on.
1. Structural and functional characterization of JmjC containing histone demethylases.
Covalent modifications of histone proteins, essential regulators of the activity of genes in eukaryotic cells, remodel the chromatin structure via a variety of enzymatic reactions. The reversible processes of some modifications, such as acetylation and deacetylation, are well characterized. Whether methylation and demethylation reversibly contribute to gene regulation, however, remains controversial. Recent studies have shown that methylation and demethylation are universally used to posttranslationally modify histones for the regulation of gene activity. In addition to LSD1, a nuclear amine oxidase homolog, which was found to function as a histone lysine demethylase, it was found that some JmjC domain-containing proteins are histone demethylases. Specifically, in collaboration with Dr. Yang Shi’s group at Harvard university, we found that members of the JMJD2 protein family are histone demethylases that act on trimethyl groups of H3-K9 and H3-K36. Moreover, some members of this family also have activity for dimethyl groups. To understand the relationships between the structures and functions of these proteins, we have determined the structure of the catalytic core of the JMJD2A protein. From this structure, several novel structure features were revealed, such as the novel JmjN domain, the JmjC domain, the C-terminal domain, and a zinc finger motif. These unique structural features create a potential catalytic center. The structure also revealed a characteristic signature motif, which includes structural determinants for cofactors such as Fe(II) and -ketoglutarate, a hallmark of non-heme containing oxygenases.
2. Characterization of Novel signal transduction mechanism through TALL-1 and its cognate receptors.
Trimer is the only functional unit for ligands of TNF family members, and trimer ligands recruit randomly distributed receptors on the membrane so as to trigger the down stream signal transduction. The novel virus-like structures of sTALL-1 with and without its cognate receptors determined in my lab are not consisted with the above common and well accepted theories. The sTALL-1 structure showed that sTALL-1 prefers existing at form of clustering with 20 trimers or 60 monomers through a novel “flap” region in vitro or vivo. Furthermore, the clustering state is the only functional unit. Structures of sTALL-1 with its cognate receptors, BCMA, BAFF-R, and TACI, showed that there are not only novel structural modules in these receptors (such as D2, X2, and others) but also novel interaction modes between ligand and receptors. These structure and interaction novelty underling novel signal transduction mechanism. Furthermore, structural modeling work on TALL-2/APRIL revealed a unique structural basis that distinglishes between sTALL-1 and APRIL for BAFF-R.
3. Structural and functional analysis of a new transcription family members.
Staphylococcus aureus (S. aureus) is a major pathogen in nosocomial bacteremia, generally accounting for ~15-20% of these bacteremic episodes. The expression of microbial virulence factors in S. aureus is a complex process that involves interactions among many gene products. Many of these virulence genes are regulated by global regulatory systems. One of them is the sar (staphylococcal accessory regulator) locus, which not only regulates the agr locus (accessory global regulator, containing protein or peptides, AgrA, AgrB, AgrC, and AgrD), but also directly controls the expression of several putative virulence determinants (e.g. hemolysins, fibrinogen and fibronectin binding proteins). A major transcription factor family plays pivotal roles in the regulation of the sar system, it is called SarA, We have determined several structures of fthe family members, SarR, SarA, and SarS etc. From these four structures, we further classified them in three sub families, SarA motif including SarA and SarR, which functions as homodime, SarS motif, which functions as monomer but contains two homolog SarA motif (as heterodimer), and RAT motif, which functions as homodimer, but contains additional helix bundle at its c-terminal.