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Contact information Recent publications Curriculum vitae Laboratory of Molecular Biology |
Biography: Sue Wickner received her Ph.D. from Albert Einstein College of Medicine where she studied biochemical mechanisms involved in DNA replication with Dr. Jerard Hurwitz. She continued working on DNA replication as a Postdoctoral Fellow with Dr. Martin Gellert at NIH, and then moved to the Laboratory of Molecular Biology in the NCI. She received a NIH Award of Merit in 1995.Research: A new concept in molecular biology that has evolved over the past ten years is that proteins fold, unfold and refold with assistance from other proteins, known as molecular chaperones. Chaperones are present in all organisms and are highly conserved; many are induced by environmental stresses such as heat shock. An exciting recent development in cell biology is the emergence of Clp/Hsp100 proteins as a new family of molecular chaperones. They are found both in eukaryotes and prokaryotes. Clp proteins participate in many cellular processes including protein reactivation, thermotolerance, DNA replication, regulation of gene expression, inheritance of prion-like factors, degradation, and membrane translocation. We discovered that Escherichia coli ClpA has molecular chaperone activity in vitro; it activates DNA binding by RepA protein of P1, like the DnaK/DnaJ/GrpE chaperone system. Activation is the ATP-dependent remodeling of inactive RepA dimers into active RepA monomers. Using another in vitro chaperone assay, we found that ClpA prevents irreversible heat inactivation of luciferase. We are trying to understand the biochemical mechanism of action of Clp chaperones. Not only are molecular chaperones of fundamental biological importance but they are medically relevant, since a number of inherited diseases are caused by aberrant protein folding reactions.There is an increasing number of new findings that implicate molecular chaperones, both directly and indirectly, in protein degradation. Some of the Clp chaperones are regulatory components of two component ATP-dependent proteases. ClpA, for example, in combination with a proteolytic component, ClpP, participates in proteolysis. We are exploring the question of how substrates, such as RepA, interact with ClpA and how they are presented to ClpP. Our working model for RepA activation by ClpA or degradation by ClpAP is shown below. The similarities between the mechanism of protein remodeling by chaperones and the mechanism of the early steps of degradation by ATP-dependent proteases suggest the possibility that the ATPase components of proteases may participate with classical chaperones in the kinetic partitioning of non-native proteins between pathways leading to reactivation, degradation or aggregation. Collaborators on this research include Marie Pak, PH.D., NIH; Joel Hoskins, M.S., NIH; Susan Gottesman, PH.D., NIH; and Michael Maurizi, Ph.D., NIH.Recent Publications: |
Contact Information: Laboratory of Molecular Biology,NCI, NIHBuilding 37, Room 2D1937 CONVENT DR MSC 4255BETHESDA MD 20892-4255Phone: 301-496-2629Fax:301-402-1344Email: suewick@helix.nih.gov
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