Zygmunt S. Derewenda

Education

  • MS, University of Lodz, Poland
  • PhD, University of Lodz, Poland
  • Postdoc, University of York, United Kingdom

Primary Appointment

  • Professor, Molecular Physiology and Biological Physics

Contact

Research Interest(s)

Mechanisms of Intracellular Signal Transduction; X-ray Crystallography

Research Description

Our primary interest is in the mechanisms by which protein molecules accomplish their diverse biological tasks. Crystallography and molecular biology are the primary tools with which we probe into the structure-function relationships in complex proteins. There are two major themes in our work: structural biology of cytoskeletal regulation and the mechanism of hydrolytic enzymes, such as esterases and thioesterases.

-------------------------------------------------------------------------------- Structural Biology of Rho-GTPase mediated signal transduction The laboratory is involved in comprehensive studies of structure-function relationships in proteins implicated in cell regulation by the Rho GTPases. We determined the crystal structure of RhoA in complex with GDP, only the second Rho GTPase to have its structure elucidated back in 1997. Subsequently we determined the molecular basis of RhoA interactions with the predominant isoform of the guanine nucleotide exchange factor (RhoGDI). We have also defined some aspects of the molecular roots of specificity in a focal adhesion associated GTPase activating protein (GAP). Our current studies focus on the structure and function of the guanine nucleotide exchange factors and similar multidomain molecules. Recently we have determined the X-ray structure of the RGSL domain of PDZRhoGEF.

Our collaborators on this project are: Drs. A.P. Somlyo, A.V. Somlyo, J.T.Parsons (UVA) and S. Gutkind (NIH). The project is currently supported by the NHLBI (NIH)

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Structure and Function in Merlin - the Neurofibromatosis Type II Gene Product.

ERM (ezrin-radixin-moesin) family of proteins are implicated in the regulation of cytoskeleton, and are thought to interact with RhoGDI (see above). Merlin, the product of the causal gene for neurofibromatosis type II, is also a member of this family. We have recently determined the structure of the N-terminal domain (N-ERMAD) of merlin at 1.8A resolution - the most accurate study to date of any member of the ERM family - and we are pursuing further aspects of structure-function relationship in this protein. Among them, we are interested in the interactions of merlin with syntenin, a protein containing a tandem of PDZ domains, and RhoGDI, which ties the project to the Rho-signaling pathways.

Collaborators: Dr. Jacek Otlewski, Wroclaw University, Poland & UVA; Current support for this project is from the Congressionally Directed Medical Research Program of the DOD.

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Structure, Function and Biology of the Proteins Involved in Neuronal Migration. One of the most active areas of research in neurosciences is neuronal migration. Because the phenomenon involves active control of the cytoskeleton, the biology is related to the general area of Rho-mediated cell regulation. PAFAH(Ib) - PAF acetylhydrolase Ib - is an oligomeric complex made up of two catalytic subunits (denoted a1 and a2) and two copies of a regulatory protein LIS1, the product of a causal gene for a genetic disorder known as the Miller-Dieker lissencephaly. Through a multifaceted, interdisciplinary study we have probed the structure-function relationships in the catalytic a subunits and we have determined several structures of homo- and heterodimers. We have also probed the catalytic function of the enzyme and the roots of substrate specificity using site directed mutagenesis. However, our current work focuses on the marker for migrating neurons - doublecortin. This is a novel MAP (microtubule associated protein), and we have both NMR and X-ray structures of specific domains, as well as data showing the mechanismof microtubule bundling by doublecortin.

Collaborating laboratories: Dr. John Bushweller, UVA; Dr. Chris Walsh, Harvard Medical Schools, Dr. Jacek Otlewski, Wroclaw University, Poland & UVA. Current support for this project is from the NINDS (NIH)

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METHODOLOGICAL PROJECTS Structural biology would not be where it is today without the revolution in methodologies, especially the new computing methods in crystallography, the advent of synchrotron radiation two decades ago, and the tools of molecular biology. We have been at the forefront of many of these developments over the course of recent years, and we continue to dedicate our efforts to the perfection of selected crystallographic techniques.

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Crystallization by Rational Surface Mutagenesis.

We believe that modifying the protein sample is a better way to ensure success in crystallization than attempting to diversify the precipitating conditions into tens of thousands of drops. We have shown that this approach gave very good results in the model system of RhoGDI, and we applied the concept to a novel structure of the RGSL domain from PDZ_containing RhoGEF. We are currently extending this approach to other proteins.

Collaborating laboratories: Dr. Zbigniew Dauter, NCI, NSLS; Dr. Jacek Otlewski, Wroclaw University, Poland & UVA. Current support for this project is from the NIGMS (NIH)

Selected Publications

  • Dziubańska P, Derewenda U, Ellena J, Engel D, Derewenda Z. The structure of the C-terminal domain of the Zaire ebolavirus nucleoprotein. Acta crystallographica. Section D, Biological crystallography. 2014;70 2420-9. PMID: 25195755 | PMCID: PMC4157450
  • Artamonov M, Momotani K, Utepbergenov D, Franke A, Khromov A, Derewenda Z, Somlyo A. The p90 ribosomal S6 kinase (RSK) is a mediator of smooth muscle contractility. PloS one. 2013;8(3): e58703. PMID: 23516539 | PMCID: PMC3596281
  • Utepbergenov D, Derewenda U, Olekhnovich N, Szukalska G, Banerjee B, Hilinski M, Lannigan D, Stukenberg P, Derewenda Z. Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 Å crystal structure of the N-terminal domain of RSK2 with bound inhibitor. Biochemistry. 2012;51(33): 6499-510. PMID: 22846040 | PMCID: PMC3462495
  • Bielnicki J, Shkumatov A, Derewenda U, Somlyo A, Svergun D, Derewenda Z. Insights into the molecular activation mechanism of the RhoA-specific guanine nucleotide exchange factor, PDZRhoGEF. The Journal of biological chemistry. 2011;286(40): 35163-75. PMID: 21816819 | PMCID: PMC3186380
  • Momotani K, Artamonov M, Utepbergenov D, Derewenda U, Derewenda Z, Somlyo A. p63RhoGEF couples Gα(q/11)-mediated signaling to Ca2+ sensitization of vascular smooth muscle contractility. Circulation research. 2011;109(9): 993-1002. PMID: 21885830 | PMCID: PMC3211138
  • Zheng M, Cierpicki T, Burdette A, Utepbergenov D, Janczyk P, Derewenda U, Stukenberg P, Caldwell K, Derewenda Z. Structural features and chaperone activity of the NudC protein family. Journal of molecular biology. 2011;409(5): 722-41. PMID: 21530541 | PMCID: PMC3159028
  • Zyłkiewicz E, Kijańska M, Choi W, Derewenda U, Derewenda Z, Stukenberg P. The N-terminal coiled-coil of Ndel1 is a regulated scaffold that recruits LIS1 to dynein. The Journal of cell biology. 2011;192(3): 433-45. PMID: 21282465 | PMCID: PMC3101096
  • Application of protein engineering to enhance crystallizability and improve crystal properties. Acta crystallographica. Section D, Biological crystallography. 2010;66 604-15. PMID: 20445236 | PMCID: PMC3089013
  • Cierpicki T, Bielnicki J, Zheng M, Gruszczyk J, Kasterka M, Petoukhov M, Zhang A, Fernandez E, Svergun D, Derewenda U, Bushweller J, Derewenda Z. The solution structure and dynamics of the DH-PH module of PDZRhoGEF in isolation and in complex with nucleotide-free RhoA. Protein science : a publication of the Protein Society. 2009;18(10): 2067-79. PMID: 19670212 | PMCID: PMC2786971
  • Derewenda U, Boczek T, Gorres K, Yu M, Hung L, Cooper D, Joachimiak A, Raines R, Derewenda Z. Structure and function of Bacillus subtilis YphP, a prokaryotic disulfide isomerase with a CXC catalytic motif . Biochemistry. 2009;48(36): 8664-71. PMID: 19653655 | PMCID: PMC2739605
  • Zheng M, Cierpicki T, Momotani K, Artamonov M, Derewenda U, Bushweller J, Somlyo A, Derewenda Z. On the mechanism of autoinhibition of the RhoA-specific nucleotide exchange factor PDZRhoGEF. BMC structural biology. 2009;9 36. PMID: 19460155 | PMCID: PMC2695464
  • Zheng M, Cooper D, Grossoehme N, Yu M, Hung L, Cieslik M, Derewenda U, Lesley S, Wilson I, Giedroc D, Derewenda Z. Structure of Thermotoga maritima TM0439: implications for the mechanism of bacterial GntR transcription regulators with Zn2+-binding FCD domains. Acta crystallographica. Section D, Biological crystallography. 2009;65 356-65. PMID: 19307717 | PMCID: PMC2659884
  • Cooper D, Boczek T, Grelewska K, Pinkowska M, Sikorska M, Zawadzki M, Derewenda Z. Protein crystallization by surface entropy reduction: optimization of the SER strategy. Acta crystallographica. Section D, Biological crystallography. 2007;63 636-45. PMID: 17452789
  • Derewenda U, Tarricone C, Choi W, Cooper D, Lukasik S, Perrina F, Tripathy A, Kim M, Cafiso D, Musacchio A, Derewenda Z. The structure of the coiled-coil domain of Ndel1 and the basis of its interaction with Lis1, the causal protein of Miller-Dieker lissencephaly. Structure (London, England : 1993). 2007;15(11): 1467-81. PMID: 17997972
  • Grembecka J, Cierpicki T, Devedjiev Y, Derewenda U, Kang B, Bushweller J, Derewenda Z. The binding of the PDZ tandem of syntenin to target proteins. Biochemistry. 2006;45(11): 3674-83. PMID: 16533050