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SINGLE-MOLECULE FLUORESCENCE STUDIES OF PROTEIN FOLDING

Award Number: R01GM080515
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: 04/01/2007
PERIOD OF PERFORMANCE END DATE: 03/31/2011

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SINGLE-MOLECULE FLUORESCENCE STUDIES OF PROTEIN FOLDING - DESCRIPTION (provided by applicant): Understanding pathways of protein folding and unfolding, and mapping partially folded intermediate states, are of utmost importance for our ability to decipher the physiology of misfolding diseases. The generation of maps of folding pathways on the energy landscapes of proteins is the long range goal of our research. Here we propose to address this goal by applying powerful single-molecule fluorescence methodology to study the folding of selected protein systems. We will use fluorescence resonance energy transfer (FRET) to follow conformational dynamics of protein molecules trapped within surface-tethered lipid vesicles, a unique method developed in our lab. Vesicles will be prepared under conditions where molecules have equal folding and unfolding rates, so that single- molecule trajectories will show frequent transitions between conformational states, including partially-folded intermediates. Analysis of trajectories will yield a wealth of information on folding pathways and rates of interconversion between folding intermediates. In addition, studies on freely-diffusing molecules will probe global structural changes of the proteins during folding. We will first study the 62 amino-acid protein L, known to be a two-state folder from bulk experiments. We will verify this observation on the single molecule level, as well as obtain structural information on the denatured state of the protein. We will also study a larger protein, adenylate kinase, which, as we already showed, possesses a very heterogeneous folding energy lansdcape. Intermediates observed during folding of this protein will be carefully mapped. A low-resolution structure of these intermdiates will be obtained by measuring several pairs of labeling sites. In a strong collaboration with Lynne Regan from Yale we will study single-molecule folding of the tetratricopeptide repeat proteins. This family of modular proteins, constructed of 34 amino-acid repeat units, has been suggested to obey a new folding paradigm, based on the classical Ising model, which predicts a large population of partially folded states near the transition midpoint. Single-molecule measurements will probe this intriguing assertion. This study will have impact on our understanding of misfolding diseases, like Alzheimer's and type II diabetes. Our experiments should help us identifying intermediate structures that act as 'weak points' during folding, leading to protein aggregates which are responsible for disease.


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: 2010 ( Subtotal = $246,035 )
2010	2010	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Biomedical Research and Research Training	000	4	2/22/2010	NON-COMPETING CONTINUATION	$246,035
														Subtotal = $246,035

Issue Date FY: 2009 ( Subtotal = $248,520 )
2009	2009	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Biomedical Research and Research Training	000	3	3/5/2009	NON-COMPETING CONTINUATION	$223,668
2009	2009	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Biomedical Research and Research Training	001	3	6/9/2009	NON-COMPETING CONTINUATION	$24,852
														Subtotal = $248,520

Issue Date FY: 2008 ( Subtotal = $248,520 )
2008	2008	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	2	3/14/2008	NON-COMPETING CONTINUATION	$248,520
														Subtotal = $248,520

Issue Date FY: 2007 ( Subtotal = $248,520 )
2007	2007	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	1	3/15/2007	NEW	$248,520
														Subtotal = $248,520

Grand Total All Awards = $991,595

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SINGLE-MOLECULE FLUORESCENCE STUDIES OF PROTEIN FOLDING

Award Number: R01GM080515

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: 04/01/2007

PERIOD OF PERFORMANCE END DATE: 03/31/2011

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