Rebecca Page | X-ray Crystallography
Rebecca Page, Principal Investigator
Department of Molecular Biology, Cell Biology and Biochemistry
My laboratory uses X-ray crystallography , NMR spectroscopy and small angle X-ray scattering (SAXS) in combination with biochemistry and genetics to understand the molecular basis of protein function, with a particular interest in understanding how bacterial signaling proteins regulate biolfim formation and antibiotic resistance, how targeting proteins direct the activity of ser/thr phosphatases and how dual specificity and tyrosine phosphatases regulate MAPK function.
Biofilms, persistence and antibiotic resistance
Bacterial biofilms are complex communities of cells containing an increased prevalence of dormant cells known as persisters, which underlie the multidrug tolerance of biofilms. However, a detailed understanding of how they assemble and how they are regulated at a molecular level is still only rudimentarily understood. Using a combination of structural, genetic and biochemical studies, we discovered that the E. coli protein mqsR, which is the most highly upregulated gene in persister cells, together with mqsA, are the defining members of an entirely new family of toxin:antitoxin systems which are essential for persistence. We are now invesitgating how the MqsA:MqsR TA system regulates biofilm formation and antibiotic resistance in vivo and new chemical tools to inhibit mqsRA mediated persistence in the cell.
PP1 holoenzymes in the nucleus
The regulation of the Ser/Thr phosphatase protein phosphatase 1 (PP1) is controlled by a diverse array of regulatory proteins. However, how these proteins direct the specificity of PP1 is not well understood. In addition, while 100’s of cell biology and biochemical reports describe key biological roles for PP1, very few structural efforts have so far been successful. We are focusing on two PP1-targeting proteins-- the nuclear ihibitor of PP1 (NIPP1) and the PP1 nuclear targeting subunit (PNUTS)--to elucidate, at a molecular level, the biological functions and modes of action of these key nuclear PP1 holoenzymes in order to provide unique novel insights into the molecular regulation of PP1.
Regulation of MAPKs by phosphatases
MAP kinases transduce environmental and developmental signals into adaptive and programmed responses. In the cell, MAPK are regulated by numerous phosphatases. For example, the hematopoietic tyrosine phosphatase (HePTP) negatively regulates T cell activation in lymphocytes via ERK2 dephosphorylation. However, only very limited structural information is available for these biologically important complexes. We are combining X-ray crystallography, NMR spectroscopy, SAXS to characterize the structures of the MAPK:PTP complexes and ITC to understand the energetics of binding.
Graduate Student Dana Lord received a travel award and was also invited to give a lecture at the 2013 American Crystallographic Association meeting in Hawaii (8/2013).
Graduate Student Dana Lord was elected to Sigma Xi, the Scientific Honor Society (4/2013). Congratulations!
The thesis of recent graduate Dr. Breann Brown was awarded the prestigous Brown Univeristy 2012 Joukowky Outstanding Dissertation Prize (5/2012).
Outreach: The 4th annual Protein Science Workshop and Lecture, a collaboration between the Page lab and the Biotechnology Certificate Program at CCRI was held.
For a full publication list, click here.
Francis et al (2011) Resting and Active States of the ERK2:HePTP Complex. JACS 133: 17138 – 17141.
Francis et al (2011) Structural basis of p38α regulation by hematopoietic tyrosine phosphatase. Nat Chem Biol 7: 916-924.
Wolfgang Peti, Ph.D., Brown University.
Lutz Tautz, Ph.D., The Burnham Institute.
Thomas Wood, Ph.D, Pennsylvania State University.