Alzheimer Disease; Membrane Proteins; Pharmacology; Crystallography, X-Ray; Chemicals and Drugs
Public Health Interests
In our laboratory we are interested in the structure and mechanism of a class of integral membrane proteins called intramembrane proteases. These proteases are involved in many important biological pathways responsible for metabolic regulation and cell signaling. The x-ray structures of rhomboid protease and GxGD protease, both solved first in our laboratory, have revealed general architectural principles for the two protease families, enabling us to ask specific questions about their mechanism of action. One question concerns how the protease changes conformation during catalysis. Since the active site of the protease is filled with water, it has to be closed initially to minimize unfavorable contact with lipids. Then how does transmembrane substrate, whose diffusion is restricted to the membrane plane, gain access to the active site? The crystal structures showed that the proteases have narrow transmembrane domains, suggesting that the lipid bilayer is severely constricted around the protein. Can this affect the presentation of buried cleavage sites to the protease? Finally, how does the protease achieve specificity? To study these questions we apply a wide array of biochemical and biophysical techniques to the two protease systems described above. The knowledge generated from these studies has both theoretical and practical significance because many membrane proteases are potential targets for pharmacological intervention.
Speciailzed Terms: Membrane protein; X-ray crystallography; Enzyme mechanism
- Xue, Y., Chowdhury, S., Liu, X., Akiyama, Y., Ellman, J. & Ha, Y. (2012) Conformational change in rhomboid protease GlpG induced by inhibitor binding to its S’ subsites. Biochemistry 51, 3723-3731.
- Xue, Y. & Ha, Y. (2012) The catalytic mechanism of rhomboid protease GlpG probed by 3,4-dichloroisocoumarin and diisopropyl fluorophosphonate. J. Biol. Chem. 287, 3099-3107.
- Hu, J., Xue, Y., Lee, S. & Ha, Y. (2011) The crystal structure of GXGD membrane protease FlaK. Nature 475, 528-531.
- Wang, Y. & Ha, Y. (2007) Open-cap conformation of intramembrane protease GlpG. Proc. Natl. Acad. Sci. U.S.A. 104,2098-2102.
- Wang, Y., Maegawa, S., Akiyama, Y. & Ha, Y. (2007) The role of L1 loop in the mechanism of rhomboid intramembrane protease GlpG. J. Mol. Biol. 374, 1104-1113.
- Wang, Y. Zhang, Y. & Ha, Y. (2006) Crystal structure of a rhomboid family intramembrane protease. Nature 444,179-183.