Our research in Academia Sinica involves the structural and functional analysis of proteins using synchrotron crystallography and other interdisciplinary approaches. In this lecture, I will present some examples which are interesting like DNA mimic proteins and useful like enzymes related to important diseases including cancers, infectious diseases, and Alzheimer disease.
DNA mimic proteins: A new paradigm for regulation of DNA functions: DNA mimic proteins (DMPs) occupy the DNA binding sites of DNA binding proteins, and prevent these sites from being accessed by DNA. To date, only a few DMPs have been reported. Several new DNA mimic proteins have been successfully identified and characterized using structural, proteomic, biochemical and bioinformatic approaches: (1) White spot syndrome virus ICP11. Functionally, ICP11 prevented DNA from binding to histone proteins and interfered with nucleosome assembly. (2) Neisseria DMP19: DMP19 used its dsDNA-like surface to interact with Neisseria transcription factor NHTF. The interaction of DMP19 and NHTF provides a novel gene regulation mechanism in Neisseria spps. (3) Neisseria DMP12: DMP12 interacts with the bacterial histone-like protein HU. The interactions between DMP12 and HU protein might play important roles in bacterial nucleoid formation, recombination, gene regulation and DNA replication. (4) S. aureus uracil DNA glycosylase inhibitor (SaUGI) has been analyzed by a combination of bioinformatics, structural and biochemical approaches. Detailed interactions will be presented.
Human glutaminyl cyclase for Alzheimer disease: N-terminal pyroglutamate (pGlu) formation is required in the maturation of proteins and bioactive peptides. The aberrant formation of pGlu may be relatedto several pathological processes, such as osteoporosis andamyloidotic diseases. This N-terminal cyclization reaction is facilitatedby the enzyme glutaminyl cyclase (QC). We have solved the crystal structuresof human QC bound with inhibitors. Our results provide a structural basis for the rational designof inhibitors against QC-associated disorders.