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Steven R. Van Doren

Associate Professor of Biochemistry
Director, Graduate Education

Email:	vandorens@missouri.edu
Phone:	(573) 882-5113
Lab:	(573) 884-6405
Fax:	(573) 882-5635
Office:	37A Schweitzer Hall
Mailing Address:	Biochemistry 117 Schweitzer Hall University of Missouri-Columbia Columbia, MO 65211
Research Areas:	Structural biology: NMR investigations of protein structure, dynamics and protein-protein interactions, particularly proteins important in inflammatory diseases.

Educational Background

BS		Oklahoma State University	Stillwater, Okla.	Biochemistry/Computer Science
PhD		University of Illinois	Urbana-Champaign, Ill.	Biophysics

Notable Honors and Service

Director of Graduate Education
Sigma Xi Excellence in Graduate Research Mentoring Award, MU chapter, 2006
American Cancer Society Research Scholar, 2003
NIH grant review panels, temporary member

Research Description

Interests. Our group is pursuing mechanisms of protein-protein interactions important in inflammatory diseases that include cancer and atherosclerosis. We are also interested in mechanisms of protein-protein interactions in innate immunity, coupling of dynamics to enzyme action, metalloproteinase specificity, and protein folding.

Approach. NMR spectroscopy is our favorite approach. It reveals structure, binding surfaces, and dynamics. We supplement NMR studies with bioinformatics, mutagenesis, enzyme kinetics, titration calorimetry, and other spectroscopy. Our mechanistic insights have been revealing key details of biological control, some of which may aid engineering of protein-protein and protein-ligand interactions with potential therapeutic applications.

Innovative results. A key theme that keeps recurring in every protein-protein interaction that we have studied is that remote parts of a protein couple to the interaction at its main binding site. For example, (i) the core of N-TIMP-1 couples to MMP-3 binding (Arumugam et al., 2003); (ii) the core of MMP-12 may adjust upon inhibitor binding (Bhaskaran et al., 2007); (iii) remote surfaces of MMP-12 contribute to its interaction with a collagen-derived, triple-helical peptide substrate (Bhaskaran et al., submitted); (iv) the core of a tumor viral J domain couples to Hsc70 binding (Garimella et al., 2006); and (v) dynamics of an FHA domain are affected by phosphopeptide binding as far as the opposite end of the domain (Ding et al., 2005). Molecular recognition can run deeper than the surface.

Innovations in methods. The group introduced a much more accurate way to map protein-protein interaction sites by NMR than commonly used chemical shift changes. The more accurate method maps exclusion of a paramagnetic probe from the interface (Arumugam et al., 1998, 2003a; Garimella et al., 2006; Bhaskaran et al., submitted). We were one of the first groups outside of NIH to refine an NMR structure of a protein and an RNA using residual dipolar couplings for greater accuracy (Wu et al., 2000; Leeper et al., 2002).

We introduced a faster way to fit steady-state enzyme kinetics parameters (k_cat and K_m) from fewer measurements than required for conventional analysis of initial velocities (Palmier and Van Doren, 2007). It can be applied to any enzyme reaction where a few progress curves can be measured. It is particularly advantageous for fluorescence data.

The laboratory’s projects are introduced below.

Metalloproteinase inhibition and specificity
Activities of matrix metalloproteinases (MMPs) foster progression of cancer, arthritis, cardiovascular disease, and other inflammatory diseases. MMP-12 is a drug target for stabilizing atherosclerotic plaques. MMP-3 a drug target for decreasing damage in the brain after stroke. TIMPs generally curb cancer progression by inhibiting MMPs and inhibiting angiogenesis. Consequently, a TIMP is being engineered to enhance its therapeutic potential. We reported NMR structures of MMP-3 (Van Doren et al., 1995), MMP-12 (Bhaskaran et al., 2007), N-TIMP-1 (Wu et al., 2000), and the complex of MMP-3 with N-TIMP-1 (Arumugam and Van Doren, 2003). Mobility of TIMP-1 contributes to MMP affinity in notable ways that include persistent slow motion of the MMP-binding ridge of TIMP-1 and binding-induced increase of dynamics in the TIMP-1 core to offset the enthalpic cost of binding (Arumugam et al., 2003; Gao et al., 2000).

Tumor viral proteins and their interactions with proteins of the host cell
We have investigated proteins that DNA tumor viruses produce to transform their mammalian host cells to foster replication of the viruses. Polyomaviruses, such as SV40 that contaminated the polio vaccines of 100 million Americans from 1955-63, produce T antigens having a DnaJ-like J domain to co-opt the Hsc70 and pRb tumor suppressors of the host cell. We reported the structure of the J domain (Berjanskii et al., 2000), described the motions of its key Hsc70-interacting loop (Berjanskii et al., 2002), mapped its interface with Hsc70’s ATPase domain, and gained insights into how T antigen uses Hsc70 to foster release of E2F transcription factors from the pRb tumor suppressor (Garimella et al., 2006).

Human papillomavirus (HPV) is a DNA tumor virus found in > 95% of cervical carcinomas. HPVs use their oncoprotein E7 to transform epithelial host cells. We have investigated its backbone’s dynamics, secondary structure, and interactions with pRb and E2F1 using NMR.

Dynamics of a Sugar-Processing Enzyme
Phosphomannomutase/phosphoglucomutase (PMM/PGM) is a key enzyme of biosynthesis of carbohydrates destined for bacterial cell surfaces and acting as virulence factors. We have embarked upon NMR of 463-residue PMM/PGM from Pseudomonas aeruginosa. (This bacterium infects cystic fibrosis patients, burn victims, and cancer patients.) The collaborating group of Lesa Beamer has illustrated the ligand-dependent conformational changes of PMM/PGM that appear to be linked to its multi-step reaction. We are seeking to learn how its dynamic fluctuations may influence its enzymatic mechanism.

Current Lab Members:

Mark Palmier, PhD candidate
Dr. R. Bhaskaran, Research Scientist
Dr. Xiangyang Liang, Research Scientist
Dr. Asokan Anbanandam, Postdoctoral Research Fellow

Undergraduate: Ms. Sneha Kumar
High schooler: Katie Van Doren

Former Long-Term Lab Members:

PhD graduates: Tom Leeper (U. of Washington), Mark Berjanskii (U. of Alberta), Gui-in Lee (Asst. Prof., Penn State-Abington), and Zhaofeng Ding (Chemistry Group Leader, Hospira, Inc.)

S. Arumugam, Guanghua Gao, Michael Riley, Bin Wu, Xin Liu, Anu Shende, Ravi Garimella, Valentyna Semenchenko, Ashley Nenninger, N. Bagegni, Jessica Blount, and Brian Patton

Research Links:

MU NMR Facility

Selected Publications

Bhaskaran R, Palmier MO, Bagegni N, Liang X, and Van Doren SR. (2007) Solution Structure of Inhibitor-Free Human Metalloelastase (MMP-12) Indicates an Internal Conformational Adjustment. Journal of Molecular Biology 374(5):1333-1344.

Palmier M and Van Doren SR. (2007) Rapid Determination of Enzyme Kinetics from Fluorescence: Overcoming the Inner Filter Effect. Analytical Biochemistry 371(1):43-51.

Ding Z, Wang H, Liang X, Morris ER, Pandit S, Skolnick J, Walker JC, Van Doren SR. (2007) Phosphoprotein and Phosphopeptide Interactions with the FHA Domain from Arabidopsis Kinase-Associated Protein Phosphatase. Biochemistry 46(10):2684-96.

Liang X, Lee G, and Van Doren SR. (2006) Partially Unfolded Forms and Non-Two-State Folding of a β-Sandwich: FHA domain from Arabidopsis Receptor Kinase-Associated Protein Phosphatase. J. Molecular Biology 364:225-240.

Garimella, R., Liu, X, Qiao, W., Liang, X., Riley, Michael I., Zuiderweg, E.R.P. and Van Doren, S.R. (2006) Hsc70 Contacts Helix III of DnaJ-like Domain from Polyomavirus T Antigens: Addressing a Dilemma in the Chaperone Hypothesis of How They Release E2F from pRb. Biochemistry 45(22):6917-6929.

Lee, G., Ding, Z., Walker, J. C., and Van Doren, S.R. (2003) NMR Structure of the forkhead-associated domain from the Arabidopsis receptor kinase-associated protein phosphatase. Proceedings of the National Academy of Sciences of the USA 100(20):11261-11266.

Arumugam, S., Gao,G., Patton, B.L., Semenchenko, V., Brew, K. and Van Doren, S.R. (2003) Increased backbone mobility in β-barrel enhances entropy gain driving binding of N- TIMP-1 to MMP-3. J. Mol. Biol., 327, 719-734.

Employment Opportunities

Post-Doctoral Opportunities

Electronic submission is encouraged, e-mail to biochemsearch@missouri.edu

Applicants should send CV and names of two references to:
Dr. Steven Van Doren
Postdoctoral Application
Biochemistry
117 Schweitzer Hall
University of Missouri-Columbia
Columbia, MO 65211

Structural biology: multi-nuclear, multi-dimensional NMR investigations of protein-protein interactions.