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Contact information Recent publications Curriculum vitae Laboratory of Molecular Biology |
Biography: Dr. Gottesman received her Ph.D. from the Department of Microbiology at Harvard University, and became a Postdoctoral Fellow at NIH. She then went to the Massachusetts Institute of Technology (MIT) as a Research Associate, and returned to NIH in 1976 as a Senior Investigator in the Laboratory of Molecular Biology.Research: We have used the ATP-dependent proteases of Escherichia coli and their targets as models for the study of the mechanism of proteolysis, the basis for target selection, and the ways in which unstable proteins are used in regulatory cascades. The primary cytoplasmic proteases in both prokaryotes and eukaryotes are energy-dependent. These proteases play essential roles in the degradation of abnormal and misfolded proteins and in the setting of appropriate levels for critical, short-lived regulatory proteins. We have focused on the Lon protease and the Clp family of proteases. Clp proteases are made up of multiple copies of an ATPase subunit (ClpX or ClpA) and a protease subunit (ClpP). Changing the ATPase subunit of the complex changes the substrate specificity, suggesting that the selection of substrates is mediated through the ATPase subunit and presumably is regulated in part by ATP hydrolysis.In examining the regulation of genes encoding the Lon substrate RcsA, we had identified a novel 85 nucleotide stable RNA, DsrA, that can overcome silencing of multiple genes in E. coli by the nucleoid-associated protein HNS. We now find that DsrA is synthesized preferentially at low temperatures and is necessary for the low temperature expression of a specialized sigma factor, RpoS. DsrA modulates RpoS synthesis by positively affecting translation of this protein by pairing with parts of the RpoS untranslated leader. The functions of DsrA in overcoming HNS silencing and in positively regulating RpoS can be separated by appropriate mutants.RpoS is also rapidly degraded during exponential growth by the ClpXP protease; this degradation is in turn regulated by the response regulator protein RssB. We have found that RssB affects degradation only of RpoS, and not of another ClpXP substrate, lambda O protein. This suggests that environmental and cell-cycle regulation via changes in protein degradation may operate by modifying substrate availability rather than protease activity. <I>In vitro</I> collaborative studies with Dr. Sue Wickner demonstrate that RssB acts directly.ClpXP and ClpAP have also been shown to be involved in the degradation of a novel set of unstable, abnormal proteins. The laboratory of Dr. R. Sauer at MIT has recently found that a stable RNA of E. coli called 10Sa RNA acts as a mobile message to direct the synthesis of an 11 amino-acid C terminal extension on the end of proteins whose synthesis is truncated; the C terminal tail then targets the proteins for rapid degradation. We found that the cytoplasmic protease primarily responsible for the degradation of a model protein of this sort is ClpXP; ClpAP also participates, and work from others suggests that a membrane-bound protease, FtsH, serves as an additional back-up. Therefore, ClpXP and ClpAP, like Lon, are involved in the degradation of abnormal proteins from the cell, and some carboxy-terminal sequences act as recognition signals for protein degradation.Collaborators on this research include Michael Maurizi, Ph.D., NIH; Sue Wickner, Ph.D., NIH; Robert Sauer, Ph.D., Massachusetts Institute of Technology; and Thomas Elliott, University of West Virginia.Recent Publications: |
Contact Information: Laboratory of Molecular Biology,NCI, NIHBuilding 37, Room 2E1837 CONVENT DR MSC 4255BETHESDA MD 20892-4255Phone: 301-496-3524Fax:301-496-3875Email: susang@helix.nih.gov
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