Zygmunt S. Derewenda, PhD
Structural biology of cell migration proteins and the Rho signaling pathway (Metastasis)
The research in the Derewenda group focuses on several projects, all of which have important impact on cancer research.
- Mechanisms of neuronal cell migration.
Cell migration is one of the key phenomena during metastasis. The details vary depending on cell and tissue type, but invariably involves remodeling of the cytoskeleton. Neuronal cells constitute an important model system, because their massive coordinated migration occurs during a specific period in fetal development as the cerebral cortex is being formed, and because of a number of genetic syndromes that have identified genes that are key to the migration. Some of these genes and protein products are thought to be endemic to the neurons, but some are found to be associated with malignant transformations and tumors in other tissues. Among the proteins which are studied in the laboratory are doublecortin and Lis1, both of which have been shown to be regulated by the glial cell-line derived neurotropic factor whose mutations lead, among other symptoms, to tumor formation. Further, other protein associated with Lis1, such as NudC, have been implicated as tumor suppressors in malignant hematopoiesis and in prostate cancer. They use a synergistic combination of molecular biology, NMR and other biophysical methods to characterize structure-function relationships that these proteins show at the molecular/atomic level.
- Structural biology of Rho GTPases and their accessory
Many tumors result from mutations in proteins involved in signaling cascades mediated by small GTPases. The GEFs, or guanine nucleotide exchange factors, are particularly well known for participating in cell transformation. They are studying the structure and function of several RhoGEFs which act downstream of G-protein coupled receptors, including PDZRhoGEF and LARG (leukemia-associated RhoGEF). Their recent work revealed the mechanism of interaction of human RhoA with the DH-PH tandem of PDZRhoGEF.
- Molecular basis of neurofibromatosis.
Neurofibromatosis type II is a debilitating disease caused by tumors in the central nervous system, due to mutations in the tumor suppressor protein merlin. They have determined the crystal structure of the FERM domain of merlin, and also studied interactions of this protein with its partners.
- Protein crystallization by surface entropy
Rational drug design requires the knowledge of the atomic structure of the target protein. It is well established that high-resolution crystal structures provide the most accurate depiction of the target. Yet, crystallization is often the limiting step, and in the case of eukaryotic proteins only a small fraction of proteins crystallizes easily. They are developing a method to overcome these proteins and to increase the success rate of protein crystallization to much higher levels. The method will also generate crystal forms that diffract to much higher resolution and therefore are more suitable for drug design purposes. This method has already been used by Merck laboratories to improve the quality of the structure of the insulin-like growth factor receptor kinase domain, which is a target for cancer chemotherapy.