Interdisciplinary Life Science - PULSe Great research is a matter of choice

Cynthia V. Stauffacher

Cynthia V.  Stauffacher Profile Picture

Professor of Biological Sciences
Ph.D.-1977- UCLA


Contact Info:

cstauffa@purdue.edu
765-494-4937


Training Group(s):
Molecular Signaling and Cancer Biology
Membrane Biology
Biomolecular Structure and Biophysics


Current Research Interests:

High resolution structural studies combined with techniques of molecular biology are beginning to reveal the workings of biological molecules at the molecular level. My research interest is in using X-ray crystallography to study the details of large macromolecular systems where a set of proteins work together to perform a biological function. Membrane proteins are often organized into these large systems and are of particular interest, as very few membrane protein structures are known.

One system we study is the family of ABC-transporters, ubiquitous membrane protein transport systems which include such medically important molecules as the multidrug resistance P-glycoprotein. We have solved the 1.6Å structure of the ATP binding cassette (RbsA) of the E. coli ribose transporter and the 3.2Å structure of the repressor protein (RbsR) which controls transcription of the rbs operon. Models of the mammalian proteins have been built which suggest how interdomain communication occurs. We are continuing to investigate the mechanism of trans-membrane transport by the RbsA/C complex, studying structures of substrate analog and inhibitor complexes.

Membrane associated enzymes also perform important biological functions, such as mammalian HMG-CoA reductase, which catalyzes the first committed step in the synthesis of cholesterol. The structure of a bacterial analogue HMG-CoA reductase has been solved at 2.2Å resolution. Difference Fourier studies have revealed the substrate binding sites, as well as a site for anti-cholesterol drug binding. Since this class of bacterial HMG-CoA reductases are found in many common pathogens, we have begun to investigate these enzymes as antibacterial drug targets.

Signal transduction in many systems is controlled by a highly regulated cascade of phosphorylation and dephosphorylation steps which begin at the membrane surface. We have solved the structures of three low molecular weight tyrosine phosphatases at high (1.6-2.2Å) resolution. We have identified the active site loop, found regions determining enzyme specificity and have investigated substrate, activator and inhibitor complexes which allow us to understand the biological mechanism at the molecular level. Additional studies in molecular detail on membrane-active toxins, such as colicin E1 and its BtuB receptor target, as well as the staphylococcal enterotoxins, which target immune cell surface molecules, will allow us to more fully understand the complex biochemistry that occurs at the membrane surface.



Selected Publications:

Tabernero, L., D. Bochar, V. W. Rodwell, and C. V. Stauffacher. 1999. Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy 3-methylglutaryl-CoA reductase. Proc. Natl. Acad. Sci. USA. 96:7167-7171.

Wang, S., Tabernero,L., M. Zhang, M., Harms, E., VanEtten, R.L. and Stauffacher, C.V. 2000. Crystal structures of a low-molecular weight protein tyrosine phosphatase from Saccharomyces cerevisiae and its complex with the substrate p-nitrophenyl phosphate. Biochemistry 39:1903-1914.

Tabernero, L., Rodwell, VW, and Stauffacher, CV. 2003. Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase. Journal of Biological Chemistry 278:19933-19938.

Zabell, A.P.R., Corden, S., Helquist, P., Stauffacher, C.V. and Wiest, O. 2004. Inhibition studies with rationally designed inhibitors of the human low molecular weight protein tyrosine phosphatase. Bioorganic and Medicinal Chemistry 12:1867-1880.

Gustafson, C.L.T., Stauffacher, C.V., Hallenga, K. and Van Etten, R.L. 2005. Solution structure of the low molecular weight protein tyrosine phosphatase from Tritrichomonas foetus reveals a flexible phosphate binding loop. Protein Science 14:2515-2525.

Steussy, C.N., Vartia, A.A., Burgner, J.W., Sutherlin, A., Rodwell, V.W., Stauffacher, C.V. 2005. X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and the complex with its second substrate/inhibitor acetoacetyl-CoA. Biochemistry 44:14256-14267.

Zabell, A.P.R., Schroff, A.D., Jr., Bain, B.E., Van Etten, R.L., Wiest, O., and Stauffacher, C.V. 2006. Crystal structure of the human B-form low molecular weight phosphotyrosyl phosphatase at 1.6Å resolution. Journal of Biological Chemistry 281:6520-6527.

Zabell, K.M., Laurence, J.S., Kinch, M.S., Knapp, D.W. and Stauffacher, C.V. 2006. Expression and purification of the intact cytoplasmic domain of the human ephrin receptor A2 tyrosine kinase in Escherichia coli. Protein Expression and Purification 47:210-216.

Steussy, C.N., Robison, A.D., Tetrick A.M., Knight, J.T., Rodwell, V.W., Stauffacher, C.V. and Sutherlin, A.L. 2006. A structural limitation on enzyme activity: The case of HMG-CoA synthase. Biochemistry 45:14407-14414..

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