Research Interests:

We use x-ray diffraction to study the structure of membrane proteins in order to understand how they carry out complex functions in cells, and how changes in these structures cause disease. We currently work on two related projects. In one project, we study Alzheimer’s amyloid precursor protein (APP) and its homologs. Proteolytic processing of APP by β- and γ-secretases generates neurotoxic amyloid β-peptide that forms senile plaques in the brain tissue. We are investigating if, and how, the structure of APP affects its cleavability by the protease, and how this influences amyloid peptide production in cells. In a second project, we study the biochemical mechanism of intramembrane proteolysis. Intramembrane proteases are highly specialized integral membrane proteins that cleave substrates within the plane of cell membranes. The presenilin/γ-secretase that cleaves APP is an intramembrane protease. Numerous mutations in the presenilin genes have been shown to cause early-onset Alzheimer’s disease. We have solved the first intramembrane protease crystal structure, and are continuing to work on the others. A long-term goal is to use the structural and mechanistic information to help develop rational therapeutic strategies for inhibiting the production of amyloid peptide in cells.

Selected References:

Wang, Y., Maegawa, S., Akiyama, Y. & Ha, Y. (2007) The role of the L1 loop in the mechanism of rhomboid intramembrane protease GlpG. J. Mol. Biol. 374, 1104-1113.

Ha, Y. (2007) Structural principles of intramembrane proteases. Curr. Opin. Struct. Biol. 17, 405-411.

Wang, Y. & Ha, Y. (2007) Open-cap conformation of intramembrane protease GlpG. Proc. Natl. Acad. Sci. U.S.A. 104,2098-2102.

Wang, Y. Zhang, Y. & Ha, Y. (2006) Crystal structure of a rhomboid family intramembrane protease. Nature 444,179-183. .

Wang, Y. & Ha, Y. (2004) The x-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Molecular Cell 15 (3), 343-353.

Gamblin, S.J., Haire, L.F., Russell, R.J., Stevens, D.J., Xiao, B., Ha, Y., Vasisht, N., Steinhauer, D.A., Daniels, R.S., Elliot, A., Wiley, D.C. & Skehel, J.J. (2004) The structure and receptor-binding properties of the 1918 influenza hemagglutinin. Science 303, 1838-1842.

Ha, Y., Stevens, D.J., Skehel, J.J. & Wiley, D.C. (2002) H5 avian and H9 swing influenza virus haemagglutinin structures: possible origin of influenza sybtypes. EMBO J. 21, 865-875.