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Sue Wickner, Ph.D.

Portait Photo of Sue Wickner
Laboratory of Molecular Biology
Head, DNA Molecular Biology Section
Senior Investigator
Center for Cancer Research
National Cancer Institute
Building 37, Room 5144
Bethesda, MD 20892


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 was elected to the National Academy of Sciences in 2004, the American Academy of Arts and Sciences in 2002, and elected a fellow of the American Association for the Advancement of Science in 2001 for her work on the biochemical mechanisms of multicomponent energy-dependent cellular machines.


Mechanisms of Action of Molecular Chaperones and the Role of Chaperones in Proteolysis

Our group studies the biochemical mechanisms of complex ATP-dependent molecular machines. Our current goal is to elucidate the mechanisms of action of energy utilizing molecular chaperones and the role of chaperones in proteolysis. Molecular chaperones are present in all organisms and are highly conserved; they participate in many, if not all, cellular processes. They interact with proteins to mediate protein remodeling, folding, assembly, and disassembly without themselves being part of the final complex. Many chaperones are induced by environmental stresses such as heat shock, oxidative stress, and heavy metals, or pathologic conditions, such as inflammation, tissue damage, infection, and genetic diseases involving mutant proteins. They play a critical role during cell stress to prevent the appearance of folding intermediates that lead to irreversibly damaged proteins and assist in the recovery from stress either by refolding and reactivating damaged proteins or by disaggregating and unfolding damaged proteins and delivering them to compartmentalized proteases. The interrelationship between stress signaling, cell death, and oncogenesis has implicated the molecular chaperones as potential targets for cancer diagnosis and treatment.

We previously discovered that Escherichia coli ClpA, an AAA+ family member and the regulatory component of ClpAP protease, has molecular chaperone activity. This finding and those of others demonstrated that Clp ATPases comprise a family of ATP-dependent chaperones. Some Clp proteins function exclusively as chaperones, while others act both as chaperones and as regulatory components of two component energy-dependent proteases. ClpB of prokaryotes and Hsp104 of yeast function solely as chaperones and are required for thermotolerance. Not only are they able to prevent stress induced protein aggregation, but in addition they are capable of reactivating insoluble proteins aggregates, a process not long ago thought to be impossible. They act in conjunction with another ATP-dependent molecular chaperone system, DnaK in prokaryotes and Hsp70 in eukaryotes. Understanding the mechanisms of action of these chaperones will provide the foundation for discovering cures and preventions for devastating diseases caused by protein aggregation and misfolding, including Alzheimer's, Parkinson's, type II diabetes, cystic fibrosis, and prion diseases.

One of our current research goals is to discover how ClpB/Hsp104 and DnaK/Hsp70 act synergistically to disaggregate insoluble proteins that neither chaperone alone is able to dissolve. We have shown that ClpB and Hsp104 have the intrinsic ability to perform some protein remodeling reactions independent of DnaK/Hsp70 and do so by a mechanism involving protein unfolding. This work and that of others suggests that polypeptides are extracted from aggregates by forcible unfolding coupled to translocation through the central channel of the ClpB/Hsp104 hexameric ring, a mechanism used by other Clp proteins to deliver polypeptides to compartmentalized proteases. To define the roles of ClpB and DnaK in protein disaggregation we are using biochemical and genetic approaches, including site-directed mutagenesis, to map regions of ClpB that are important for its collaboration with DnaK.

Another aim of our group is to explore the mechanism of action of two Clp ATPases, ClpA and ClpX, in proteolysis in combination with ClpP, the proteolytic component of the ClpAP and ClpXP proteases. More specifically we recently discovered that ClpXP participates in cell division of E. coli. We have shown that FtsZ, the major cytoskeletal protein in bacteria and a tubulin homolog, is degraded by ClpXP. In wild type cells FtsZ performs a central role in cell division by polymerizing and forming a Z-ring at midcell where division occurs. In a clpX deletion mutant, FtsZ is turned over slower than in the wild-type strain and overexpression of ClpXP results in increased FtsZ degradation and filamentation of cells. In vitro, both FtsZ protomers and polymers are degraded by ClpXP; however, polymerized FtsZ is degraded more rapidly than the monomer. We are currently testing the hypothesis that ClpXP participates in cell division by modulating the equilibrium between free and polymeric FtsZ via degradation of FtsZ filaments and protomers.

Our group is also studying how regulatory proteins act to target specific substrates for degradation by Clp proteases. We are examining the regulation of degradation of the E. coli stationary phase sigma factor, sigma S, by a response regulator protein, RssB, in conjunction with the ClpXP protease in collaboration with Susan Gottesman's laboratory (NCI). ClpXP alone degrades sigma S poorly and RssB greatly stimulates the reaction. Dissecting the reaction into partial reactions is underway to understand how this unique targeting protein, whose own activity is modulated by phosphate transfer reactions, regulates proteolysis by catalyzing the presentation of a specific substrate to a specific protease.

This page was last updated on 12/12/2013.