Derewenda, Zygmunt S.

Zygmunt S. Derewenda

Zygmunt S. Derewenda

Primary Appointment

Professor, Molecular Physiology and Biological Physics

Education

  • PhD, Chemistry, University of Lodz, Poland
  • Postdoc, Protein Crystallography, University of York, United Kingdom
  • MS, Biochemistry, University of Lodz, Poland

Contact Information


Telephone: 434-243-6842
Email: zsd4n@virginia.edu
Website: http://www.people.virginia.edu/%7Ezsd4n/Website/Laboratory_home.html

Research Interests

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.

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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 without the new computing methods in crystallography, advent of synchrotron radiation two decades ago, and the tools of molecular biology. We have been at the forefront of many of these development over the course of the last 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