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INTERPHOTORECEPTOR RETINOID BINDING PROTEIN: STRUCTURE AND FUNCTION

Award Number: R01EY009412
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1993
PERIOD OF PERFORMANCE END DATE: 08/31/2012

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INTERPHOTORECEPTOR RETINOID BINDING PROTEIN: STRUCTURE AND FUNCTION - DESCRIPTION (provided by applicant): Interphotoreceptor retinoid-binding protein (IRBP), the major soluble protein component of the interphotoreceptor matrix (IPM), has access to M¿ller cells, photoreceptors, and RPE. The mechanism by which IRBP protects retinoids from isomeric and oxidative degradation while targeting their delivery/release between the above cells during the visual cycle is poorly understood. Our long-term goal is to understand at the molecular level how IRBP accomplishes its remarkable functions. The mechanism underlying IRBP's function or role in disease remains unknown because little is understood about its structure-function relationships. Its structure is unusual being composed of tandem homologous "modules" each ~300 residues in length. Although the individual modules have some functional activity, they are not equivalent, and important interactions take place between them. A critical gap is that little is known about the structure of the full-length protein and quaternary association of the "modules". However, obtaining IRBP at the concentrations needed for X-ray crystallography has been problematic as the protein denatures and precipitates when concentrated above 3 mgs/ml. In the current funding period, we purified to homogeneity full-length bovine, xenopus, human and zebrafish IRBPs in stable and functionally active pristine forms, devoid of fusion tags. These protein solutions can now be readily concentrated without denaturation or precipitation. We have optimized conditions for growing diffraction-quality crystals of these full-length IRBPs. Preliminary structure elucidation analysis for Xenopus IRBP suggests that the single module structure may be substantially modified in the full-length functional protein. Analyses of the expression, purification, stability, crystallization, ligand-binding, anti-oxidant activity, and homology-modeling data on these IRBPs have led to our hypothesis that quaternary association of the "modules" contributes to the structural scaffold(s) that bind and protect retinoids from degradation, and that the "modules" contribute unequally in these roles as well as in target retinoid delivery and release at the cell surface. This hypothesis will be evaluated through the following complementary aims. Aim 1: To determine the crystal structures of IRBPs composed of four modules (human, bovine, Xenopus), and two modules (zebrafish). Aim 2: To define binding-interactions of physiologically relevant ligands with IRBP and elucidate the molecular basis of IRBP's protective/anti-oxidant roles. Aim 3: To determine how IRBP efficiently targets retinoid removal/delivery. Aim 4: To determine the structural and functional "hot-spots" in IRBP. PUBLIC HEALTH RELEVANCE: The mechanism by which IRBP protects retinoids from isomeric and oxidative degradation while targeting their delivery/release between photoreceptors, retinal pigmented epithelium and M¿ller cells during the visual cycle is poorly understood. A critical gap is that little is known about the structure of the full-length protein and quaternary association of the "modules" that comprise the structure of IRBP. Analyses of the expression, purification, stability, crystallization, ligand-binding, anti-oxidant activity, and homology-modeling data on these IRBPs have led to our hypothesis that quaternary association of the "modules" contributes to the structural scaffold(s) that bind and protect retinoids from degradation, and that the "modules" contribute unequally in these roles as well as in targeting retinoid delivery and release at the cell surface.


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: 2011 ( Subtotal = $378,621 )
2011	2011	SUNY, BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	17	8/8/2011	NON-COMPETING CONTINUATION	$378,621
														Subtotal = $378,621

Issue Date FY: 2010 ( Subtotal = $390,452 )
2010	2010	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	16	8/9/2010	NON-COMPETING CONTINUATION	$390,452
														Subtotal = $390,452

Issue Date FY: 2009 ( Subtotal = $394,396 )
2009	2009	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	004	15	9/11/2009	NON-COMPETING CONTINUATION	$394,396
2009	2008	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	003	14	9/7/2009	COMPETING CONTINUATION	$400,896
2009	2008	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	002	14	9/3/2009	COMPETING CONTINUATION	-$400,896
2009	2008	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	001	14	8/28/2009	COMPETING CONTINUATION	$400,896
2009	2008	STATE UNIVERSITY OF NEW YORK AT BUFFALO	219 MARKLE HALL	BUFFALO	NY	10016		USA	Vision Research	000	14	8/25/2009	COMPETING CONTINUATION	-$400,896
														Subtotal = $394,396

Issue Date FY: 2008 ( Subtotal = $400,896 )
2008	2008	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	PO BOX 9	ALBANY	NY	12201	ALBANY	USA	Vision Research	000	14	9/1/2008	COMPETING CONTINUATION	$400,896
														Subtotal = $400,896

Issue Date FY: 2006 ( Subtotal = $218,904 )
2006	2006	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	13	9/13/2006	NON-COMPETING CONTINUATION	$218,904
														Subtotal = $218,904

Issue Date FY: 2005 ( Subtotal = $224,257 )
2005	2005	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	12	6/27/2005	NON-COMPETING CONTINUATION	$224,257
														Subtotal = $224,257

Issue Date FY: 2004 ( Subtotal = $225,325 )
2004	2004	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	11	9/16/2004	NON-COMPETING CONTINUATION	$225,325
														Subtotal = $225,325

Issue Date FY: 2003 ( Subtotal = $228,300 )
2003	2003	SUNY, BUFFALO	UB Commons, Ste 211	AMHERST	NY	14228	ERIE	USA	Vision Research	000	10	9/8/2003	COMPETING CONTINUATION	$228,300
														Subtotal = $228,300

Issue Date FY: 2002 ( Subtotal = $176,561 )
2002	2002	SUNY, BUFFALO	3435 MAIN STREET, ABBOTT ANNEX	BUFFALO	NY	14214	ERIE	USA	Vision Research	000	9	9/30/2002	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$176,561
														Subtotal = $176,561

Issue Date FY: 2001 ( Subtotal = $168,469 )
2001	2001	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Vision Research	000	8	9/12/2001	NON-COMPETING CONTINUATION	$168,469
														Subtotal = $168,469

Issue Date FY: 2000 ( Subtotal = $178,704 )
2000	2000	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Vision Research	000	7	8/23/2000	NON-COMPETING CONTINUATION	$178,704
														Subtotal = $178,704

Issue Date FY: 1999 ( Subtotal = $207,409 )
1999	1999	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Vision Research	000	6	8/27/1999	COMPETING CONTINUATION	$207,409
														Subtotal = $207,409

Grand Total All Awards = $3,192,294

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INTERPHOTORECEPTOR RETINOID BINDING PROTEIN: STRUCTURE AND FUNCTION

Award Number: R01EY009412

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1993

PERIOD OF PERFORMANCE END DATE: 08/31/2012

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