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STRUCTURAL AND DYNAMICS IN ALLOSTERIC GENE REGULATION

Award Number: R01GM077234
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2014

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STRUCTURAL AND DYNAMICS IN ALLOSTERIC GENE REGULATION - DESCRIPTION (provided by applicant): Tight control over gene expression is critical for normal cellular development, response to environmental signals, growth and proliferation. The broad, long-term objective of the proposed research is to understand the mechanisms by which cells use ligand-protein and protein-protein interactions to allosterically regulate gene expression. To understand allosteric gene regulation we have chosen a biochemically tractable gene regulatory system in Bacilli: control of tryptophan biosynthesis genes by the oligomeric TRAP and Anti-TRAP proteins. Specifically, this proposal focuses on characterizing the structural and dynamic basis for (1) positive regulation of the ring-shaped TRAP 11-mer protein by its allosteric activator, tryptophan, and (2) negative regulation of TRAP by the Anti-TRAP 3-/12-mer. I. We hypothesize that tryptophan binding activates TRAP by altering the protein's dynamic behavior. We will test this hypothesis by comparing the solution structures (aim 1) and dynamics and thermodynamics (aim 2) of apo and Trp-activated TRAP, as well as a constitutively active mutant, and by measuring the kinetics of TRAP activation (aim 3). We will employ NMR spectroscopy and small angle X-ray scattering (SAXS) to determine solution structure and dynamics, and calorimetric and spectroscopic methods to characterize thermodynamics and kinetics of tryptophan-mediated TRAP activation. II. We hypothesize that Anti-TRAP (AT) binds TRAP in an asymmetric fashion and that protein dynamics is critical for specific recognition of undecameric (11-mer) TRAP by trimeric/dodecameric AT. To provide insight into the mechanism of TRAP inactivation by AT, we will (aim 4) characterize the solution structure and dynamics of AT, (aim 5) study their interaction and develop a three-dimensional model of the TRAP-AT complex. Understanding the control of gene expression is a crucial step toward elucidating the molecular mechanisms of many diseases caused by improper gene regulation, such as cancer. Protein dynamics and allostery are intimately linked; therefore, mechanistic understanding of how regulation is achieved by changing protein behavior will help us to understand and ultimately control gene expression as part of a therapeutic strategy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	3/18/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	6/13/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $282,945 )
2010	2010	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	4	5/10/2010	NON-COMPETING CONTINUATION	$282,945
														Subtotal = $282,945

Issue Date FY: 2009 ( Subtotal = $285,803 )
2009	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	3	5/21/2009	NON-COMPETING CONTINUATION	$285,803
														Subtotal = $285,803

Issue Date FY: 2008 ( Subtotal = $288,006 )
2008	2008	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	2	5/23/2008	NON-COMPETING CONTINUATION	$288,006
														Subtotal = $288,006

Issue Date FY: 2007 ( Subtotal = $316,695 )
2007	2007	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	7/16/2007	NEW	$316,695
														Subtotal = $316,695

Grand Total All Awards = $1,173,449

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STRUCTURAL AND DYNAMICS IN ALLOSTERIC GENE REGULATION

Award Number: R01GM077234

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2014

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