Andrew VanDemark

  • Associate Professor
  • Structural biology

Contact

Office: (412) 648-0110
Lab: (412) 648-0110
A360 Langley Hall
4249 Fifth Avenue
Pittsburgh, PA 15260

We use a variety of techniques including X-ray crystallography to discover at the molecular level how proteins function, how they are regulated, and to unlock the mechanism underlying their function. We are interested in the structure, function, and assembly of protein-protein and protein-DNA interactions. We have an active research interest in several areas:

Paf1 Complex

Eukaryotic gene transcription is an essential and highly regulated process that is dependent on a large set of protein factors centered around the enzyme RNA polymerase II (Pol II).    The Paf1 complex (Pol II Associated Factor 1) is a 5-subunit transcription elongation factor, conserved from yeast to humans, that travels with the elongating polymerase and is required for the maintenance of histone modifications, the recruitment of RNA processing factors and the communication with transcriptional activators. Mutation or deletion of Paf1C subunits is associated with a variety of cancers, including leukemia and parathyroid tumors, underscoring its biological importance. How the Paf1 complex coordinates its many activities is unknown. Our work is focused on understanding the architecture and function of this complex.

Mechanisms of site-specific integration/excision

Temperate bacteriophages usually form lysogens, where the prophage genome is integrated into (or excised from) the host chromosome by an array of proteins, most notably the phage-encoded integrases.  We are looking to understand how serine-integrases, which have unusually large and complex DNA binding domains, recognize their DNA targets and direct the integration mechanism. Additionally, we are interested in understanding the structural differences between the integration and excision synaptic complexes. We are studying this through an exploration of novel Xis proteins which are protein factors that bend DNA and direct the formation of the excisive synaptic complex.

Mechanisms of Shroom-mediated apical constriction

Defects in neural tube closure during development are among the most common of birth defects, striking about 1 in 1,000 live births. The actin-binding protein Shroom is essential for neural tube closure in a variety of vertebrate organisms by establishing an actomyosin network at the apical surface of polarized epithelial cells, and through the process of apical constriction inducing changes in cell shape that facilitate development. A novel domain at the C-terminus of Shroom, called SD2, is required for apical constriction. We are looking to discover the mechanism by which the SD2 domain interacts with its binding partner Rho-kinase to facilitate apical constriction.

E-mail Lab

Mohan, S., Das, D., Bauer, RJ, Heroux, A., Zale

Mohan, S., Das, D., Bauer, RJ, Heroux, A., Zalewski, J.K., Heber, S., Dosunmu-Ogunbi, A.M., Trakselis, M.A., Hildebrand, J.D., VanDemark, A,P. (2013) Structure of a highly conserved domain of Rock1 required for Shroom-mediated regulation of cell morphology. PLoS One 8(12):e81075

Singh. S., Rockenbach, K., Dedrick, R. M., VanD

Singh. S., Rockenbach, K., Dedrick, R. M., VanDemark, A. P., & Hatfull, G. F. (2014) Cross-talk between Diverse Serine Integrases. J Mol Biol 426, 318-331.

Singh, S., Plaks, S. G., Homa, N. J., Amrich, C

Singh, S., Plaks, S. G., Homa, N. J., Amrich, C. G., Heroux, A., Hatfull, G. F., & VanDemark, A. P. (2014). The structure of Xis reveals the basis for filament fomration and insight into DNA bending within a mycobacteriophage Intasome.  J. Mol. Biol., 426, 412-422.

Wier, A.D., Mayekar, M.K., Heroux, A., Arndt, K

Wier, A.D., Mayekar, M.K., Heroux, A., Arndt, K.M., VanDemark, A.P. (2013) The structural basis for Spt5-mediated recruitment of the Paf1 complex to chromatin. Proc. Natl. Acad. Sci. USA 110:17290-17295

Roland, B.P., Stuchul, K.A., Larsen, S.B., Amri

Roland, B.P., Stuchul, K.A., Larsen, S.B., Amrich, C.G., VanDemark, A.P., Celotto, A.M., and Palladino, M.J. (2013). Evidence of a triosephosphate isomerase non-catalytic function critical to behavior and longevity. Journal of Cell Science. ePub

Godin, S., Wier, A., Kabbinavar, F., Bratton-Pa

Godin, S., Wier, A., Kabbinavar, F., Bratton-Palmer, D.S., Ghodke, H., Van Houten, B., VanDemark, A.P., and Bernstein, K.A. (2013). The Shu complex interacts with Rad51 through the Rad51 paralogues Rad55-Rad57 to mediate error-free recombination. Nucleic Acids Research 41, 4525-4534

Celotto, A.M., Liu, Z., VanDemark, A.P., and Pa

Celotto, A.M., Liu, Z., VanDemark, A.P., and Palladino, M.J. (2012). A novel Drosophila SOD2 mutant demonstrates a role for mitochondrial ROS in neurodevelopment and disease. Brain and Behavior 2, 424-434

Mohan S, Rizaldy R, Das D, Bauer RJ, Heroux A,

Mohan S, Rizaldy R, Das D, Bauer RJ, Heroux A, Trakselis MA, Hildebrand JD, VanDemark AP (2012) Structure of the Shroom Domain 2 reveals a three-segmented coiled-coil required for dimerization, Rock binding, and apical constriction. . Mol Biol Cell. 22:795-805    PMCID: PMC3364177

Amrich CG, Davis CP, Rogal WP, Shirra MK, Herou

Amrich CG, Davis CP, Rogal WP, Shirra MK, Heroux A, Gardner RG, Arndt KM, VanDemark AP (2012) Structure of the Cdc73 subunit of the Paf1 complex contains a C-terminal Ras-like domain that promotes association of the Paf1 complex with chromatin. J.Biol Chem 287: 10863-10875

D'Aiuto L, Marzulli M, Mohan KN, Borowczyk E, S

D'Aiuto L, Marzulli M, Mohan KN, Borowczyk E, Saporiti F, VanDemark AP, Chaillet JR (2010) Dissection of structure and function of the N-terminal domain of Mouse DNMT1 using Regional Frameshift Mutagenesis PLoS One 5:e9831

VanDemark, A.P., H. Xin, L. McCullough, R. Rawlins, S. Bentley, A. Heroux, D.J. Stillman, C.P. Hi

VanDemark, A.P., H. Xin, L. McCullough, R. Rawlins, S. Bentley, A. Heroux, D.J. Stillman, C.P. Hill, and T. Formosa (2008) Structural and functional analysis of the Spt16p N-terminal domain reveals overlapping roles of yFACT subunits. J. Biol. Chem. 283:5058-5068

Welch, B., A.P. VanDemark, A. Heroux, C.P. Hill, and M.S. Kay (2007) Potent D-peptide inhibitor o

Welch, B., A.P. VanDemark, A. Heroux, C.P. Hill, and M.S. Kay (2007) Potent D-peptide inhibitor of HIV-1 entry. Proc. Natl. Acad. Sci., USA :

VanDemark, A.P., M. Kasten, E. Ferris, A. Heroux, C.P. Hill, and B.R. Cairns (2007) Autoregulatio

VanDemark, A.P., M. Kasten, E. Ferris, A. Heroux, C.P. Hill, and B.R. Cairns (2007) Autoregulation of the Rsc4 Tandem Bromodomain by Gcn5 acetylation. Mol. Cell :In Press

VanDemark, A.P., M. Blanksma, E. Ferris, A. Heroux, C.P. Hill, and T. Formosa (2006) The structur

VanDemark, A.P., M. Blanksma, E. Ferris, A. Heroux, C.P. Hill, and T. Formosa (2006) The structure of the yFACT Pob3-M domain, its interaction with the DNA replication factor RPA, and a potential role in nucleosome deposition. Mol. Cell 22:363-374

Macbeth, M.R., H.L. Schubert, A.P. Vandemark, A.T. Lingam, C.P. Hill, and B.L. Bass (2005) Inosit

Macbeth, M.R., H.L. Schubert, A.P. Vandemark, A.T. Lingam, C.P. Hill, and B.L. Bass (2005) Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309:1534-1539

VanDemark, A.P., and C.P. Hill (2005) E1 on the move. Mol. Cell 17:474-

VanDemark, A.P., and C.P. Hill (2005) E1 on the move. Mol. Cell 17:474-475

VanDemark, A.P., and C.P. Hill (2004) Grabbing E2 by the tail. Nat. Struct. Mol. Biol.

VanDemark, A.P., and C.P. Hill (2004) Grabbing E2 by the tail. Nat. Struct. Mol. Biol. 11:908-909

VanDemark, A.P., and C.P. Hill (2003) Two-stepping with E1. Nat. Struct. Biol. 1

VanDemark, A.P., and C.P. Hill (2003) Two-stepping with E1. Nat. Struct. Biol. 10:244-246

VanDemark, A.P., and C.P. Hill (2002) Structural basis of ubiquitylation. Curr. Opin. Struct.

VanDemark, A.P., and C.P. Hill (2002) Structural basis of ubiquitylation. Curr. Opin. Struct. Biol. 12:822-830

VanDemark, A.P., and C.P. Hill (2002) SUMO wrestling with specificity. Structure

VanDemark, A.P., and C.P. Hill (2002) SUMO wrestling with specificity. Structure 10:281-282

VanDemark, A.P., R.M. Hofmann, C. Tsui, C.M. Pickart, and C. Wolberger (2001) Molecular insights

VanDemark, A.P., R.M. Hofmann, C. Tsui, C.M. Pickart, and C. Wolberger (2001) Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer. Cell 105:711-720

Pickart, C.M., and A.P. VanDemark (2000) Opening doors into the proteasome. Nat. Struct. Biol

Pickart, C.M., and A.P. VanDemark (2000) Opening doors into the proteasome. Nat. Struct. Biol. 7:999-1001

Jabet, C., E.R. Sprague, A.P. VanDemark, and C. Wolberger (2000) Characterization of the N-termin

Jabet, C., E.R. Sprague, A.P. VanDemark, and C. Wolberger (2000) Characterization of the N-terminal domain of the yeast transcriptional repressor Tup1. Proposal for an association model of the repressor complex Tup1 x Ssn6. J. Biol. Chem. 275:9011-9018
Dr. VanDemark received his Ph.D. in 2001 with Cynthia Wolberger at Johns Hopkins University, performed his postdoctoral research with Christopher Hill at the University of Utah, and joined the Department in 2007.