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3203 Southeast Woodstock Boulevard, Portland, Oregon 97202-8199

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This Thursday’s Chemistry Department Seminar speaker is:


Richard Brennan, Ph.D

James B. Duke Professor of Biochemistry; Chair, Dept. of Biochemistry; Duke University

“A Novel RNA Polymerase Underlies the Pathogenicity of Francisella Tularensis

Thursday, October 11, 2018

4:15 pm Seminar begins

Biology 19


Francisella tularensis, the aetiological agent of tularemia, is one of the most pathogenic and infectious bacteria known.  Indeed, inhalation of just ten bacteria will result in disease.  As such, Francisellais classified as a category A bioweapon by the U.S. government.  Key to F. tularensispathogenicity is the set of genes encoded primarily on the FrancisellaPathogenicity Island (FPI).  In addition to RNA polymerase, the expression of these genes requires three regulatory proteins: the heterodimeric macrophage growth locus protein A (MglA)-stringent starvation protein A (SspA) complex, and the transcription activator, and the pathogenicity island gene regulator (PigR). Critically, the bacterial small molecule alarmone, ppGpp, which is produced during infection, is also required to initiate and coordinate Francisellavirulence.  Recently, we discovered that MglA-SspA binds ppGpp with high affinity and the ((MglA-SspA)-ppGpp) complex binds PigR.  Our structural, biochemical and in vivo studies provided detailed insight into the novel mechanism of ppGpp binding and the recruitment of PigR to this complex. Intriguingly, the FrancisellaRNA polymerase is unique in that MglA-SspA are a constitutive subunit of this enzyme. This finding links the binding of ppGpp to the MglA-SspA complex, and consequential binding of PigR to the ((MglA-SspA)-ppGpp) complex, to the recruitment of polymerase to the PigR-regulated promoters of the FPI and other genes critical to the virulence of this bacterium.  However, the structural organization of the RNAP-((MglA-SspA)-ppGpp)-PigR complex remains unclear as does the molecular mechanism by which this complex is recruited to cognate FPI promoters.  To begin to address these issues we have undertaken a series of structural and biochemical studies on this complex.  Here, we describe the first high-resolution structure of a Francisella tularensisRNAP-(MglA-SspA)-DNA complex, which reveals its novel quaternary structure and provides insight into the mechanism of its recruitment to the FPI by PigR.


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