Pia Vogel

Pia Vogel

Professor

Biological Sciences

Contact

Office: DLSB 233
Email: pvogel@smu.edu

Educational Background

Ph.D. University of Kaiserlautern

About

Lab: DLSB 221
Tel: 214-768-1785

Email: pvogel@smu.edu

Research Interests

Structure, Molecular Dynamics and Protein-Protein Interactions of Nucleotide Binding Proteins
F1Fo -ATP-Synthase
Multidrug Resistance Proteins
Ryanodine Receptor
ATP Synthase: Protein-Protein Interactions

The intriguing mechanism of ATP formation or hydrolysis by the FoF1-ATP synthase, Nature’s most powerful and efficient rotary motor, has challenged a great number of scientists worldwide over the last three decades. The importance of this type of basic research was shown when the Nobel Prize in Chemistry 1997 was awarded to two outstanding scientists of the field, Paul D. Boyer and John E. Walker, for their accomplishments in studying this enzyme. 

I have studied F1-ATPase for more than 20 years using a number of different approaches. Since a structure for the mitochondrial F1-ATPase was solved in 1994 by John Walker's laboratory and the rotational motion of the internal γ-subunit of the enzyme can be observed in real time in the experiments from Masasuke Yoshida's laboratory, the questions that are still intriguing and unresolved center around the mechanism of energy-transduction during proton translocation and ATP synthesis or hydrolysis.

My group is focusing on the interactions and the structure of the so-called external stalk of the ATPsynthase that is thought to stabilize the enzyme complex and may be involved in elastic energy coupling between the proton-driven rotation of membrane embedded subunits of the enzyme and the rotation of the internal γ-subunit that causes the binding and release of substrate (ADP) and product (ATP).

Using the powerful Electron Spin Resonance Spectroscopy (ESR), we employ site-specific spin labeling of either the whole enzyme or the potential "stator-subunit" b to elucidate structural and dynamic information. Heavy use is made of state-of-the-art molecular modeling techniques. The data collected in the lab are used to validate structural models created on our two Linux computer clusters.

Multi-Drug Resistance: Regulation, Structure and Function

The family of ABC-type ATPases performs a wide variety of transport processes across cellular membranes. Transport substrates range from import-substrates like nutrients, e.g. sugars, ions and amino acids, to export-substrates like drugs and other hydrophobic, mostly cell-toxic substances. Some members of this family, like the first discovered member MDR1 or P-glycoprotein, are especially problematic in the treatment of human diseases like cancer and AIDS by conferringmultidrug resistance to the respective anti-cancer and anti-AIDS drug.

Although high-resolution structures exist for some of the bacterial transporters, much remains to be learned about their molecular mechanisms and the protein dynamics that are key to the enzyme mechanisms. Such information will be extremely valuable even if an X-ray structural model became available in the near future for the human protein. In our group we perform a variety of highly innovative experiments using ESR spectroscopy combined with spin-labeled nucleotides and site-specific spin labeling to further our understanding of the molecular mechanisms that underlie the function of this medically greatly relevant enzyme. We currently study the human drug resistance proteins MDR1 and the MRPs 2 and 3.

Ryanodine Receptor: Structure and Function

Many fundamental biological processes in cells depend on and function as a response to intracellular calcium concentration. Ca2+-release through specific channels is therefore an important signal transduction pathway. One pharmacologically important group of Ca2+ -release channels are the different subtypes of ryanodine receptors that are found in skeletal and cardiac muscle as well as the brain. 

We have recently discovered a potentially novel pathway for the regulation of calcium channels like the ryanodine sensitive Ca-channel, ryanodine receptor 1 (RyR1), using Electron Spin Resonance spectroscopy (ESR) and spin-labeled ATP. Employing this technique we for the first time unequivocally showed that the homo-tetrameric channel contains a total of eight ATP-binding sites and that the accessibility and affinity of these binding sites is directly regulated by divalent cations like Mg2+ and Ca2+.

Scientific Accomplishments

In the past several years my laboratory group has successfully studied nucleotide-binding proteins and enzymes, such as ATPases from different organisms, members of the important family of chaperones as well as the group of p21ras- like small G-proteins. My group uses ESR spectroscopy as a very powerful technique to study the enzymes and proteins. ESR has the advantage of yielding information about conformational differences or transitions within proteins in solution and therefore allows the evaluation of protein dynamics. In addition we are able to obtain structural information upon evaluation of dipolar interaction of bound radicals as well as information about nucleotide binding characteristics of the proteins, such as substrate binding stoichiometries and affinities. In addition to being able to generate mutants, express, isolate and characterize desired proteins, my group also chemically synthesizes some of the needed reporters (spin labels and spin-labeled nucleotides). We also perform our biophysical investigations in our own lab. We are active in a number of very productive collaborative projects that broaden our research spectrum.

Selected Publications

“Subunit b dimer of the Escherichia coli ATP synthase can form left-handed coiled coils”, John G. Wise and Pia D. Vogel, (2007) submitted

“Structure of the Cytosolic Part of the Subunit b-Dimer of Escherichia coli FoF1-ATP Synthase”, Tassilo Hornung, Oleg A. Volkov, Tarek M. A. Zaida, Sabine Delannoy, John G. Wise and Pia D. Vogel, (2007) submitted

“Insights into the Regulation of the Ryanodine Receptor: Differential Effects of Mg2+ and Ca2+ on Nucleotide Binding”, Dias, J.M., Szegedi, C, Jóna, I., and Vogel, P.D. (2006) Biochemistry 45, 9408 – 9415