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Structural basis for chaperone-dependent folding of beta-propeller proteins essential for vision

Award Number: R01EY012287
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/03/1999
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Structural basis for chaperone-dependent folding of beta-propeller proteins essential for vision - PROJECT SUMMARY The cytosolic chaperonin CCT is a large protein complex that plays an indispensable role in maintaining the cellular proteome by assisting in the folding of numerous proteins with complex tertiary structures and unfavorable folding trajectories. Proper CCT function is vital to human vision as evidenced by the fact that inactivating mutations in CCT cause Leber Congenital Amaurosis (LCA). CCT contributes to the visual process by folding the cytoskeletal proteins actin and tubulin as well as a number of proteins with b-propeller folds that have essential functions in the visual process. These include the G protein b1 (Gb1) subunit of the visual G protein transducin, the G protein b5 (Gb5) subunit of the regulator of G protein signaling 9 (RGS9) dimer, and the BBS2, BBS7 and BBS9 subunits of the Bardet-Biedl syndrome (BBSome) ciliary transport complex. In this proposal, we present evidence for a new function of CCT in the folding of human RPE65, another b-propeller protein that is a key enzyme in the visual cycle, the process that converts the all-trans retinol product of the light response back to 11-cis retinal to regenerate rhodopsin and maintain vision. Despite the importance of CCT in maintaining the proteome, we know very little at the molecular level about how CCT assists in the folding of these b-propeller proteins and how mutations in these proteins disrupt folding and cause disease. To address this gap in knowledge, we propose to use high resolution cryo-EM to determine the structures of key intermediates in the folding of human RPE65 and Gb5. These structures will tell us at the molecular level how CCT interacts with RPE65 and Gb5 to enable their folding. Furthermore, we propose to determine the structure of RPE65 and Gb5 folding mutants bound to CCT to learn how the mutations disrupt the folding trajectory and trap the mutant proteins inside CCT in an unfolded state. These studies will provide new insight into the molecular defects that cause misfolding of the RPE65 and Gb5 mutants and will establish a foundation for structure-based drug design to create new therapies for LCA and other retinopathies caused by these mutations.


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: 2025 ( Subtotal = -$5,751 )
2025	2022	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	20	2/26/2025	SUPPLEMENT FOR EXPANSION	-$804
2025	2022	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	20	2/26/2025	NON-COMPETING CONTINUATION	-$4,947
														Subtotal = -$5,751

Issue Date FY: 2022 ( Subtotal = $448,596 )
2022	2022	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	19	3/7/2022	SUPPLEMENT FOR EXPANSION	$16,435
2022	2022	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	002	20	7/8/2022	SUPPLEMENT FOR EXPANSION	$46,273
2022	2022	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	20	7/7/2022	NON-COMPETING CONTINUATION	$385,888
														Subtotal = $448,596

Issue Date FY: 2021 ( Subtotal = $385,887 )
2021	2021	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	003	19	6/30/2021	NON-COMPETING CONTINUATION	$385,887
2021	2020	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	18	3/3/2021	COMPETING CONTINUATION	$0
2021	2020	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	18	3/19/2021	COMPETING CONTINUATION	$0
2021	2019	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	002	17	6/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $385,887

Issue Date FY: 2020 ( Subtotal = $416,072 )
2020	2020	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	18	9/7/2020	COMPETING CONTINUATION	$416,072
2020	2019	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	17	8/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,072

Issue Date FY: 2019 ( Subtotal = $348,000 )
2019	2019	BRIGHAM YOUNG UNIVERSITY	A-41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	17	12/24/2018	NON-COMPETING CONTINUATION	$348,000
														Subtotal = $348,000

Issue Date FY: 2018 ( Subtotal = $348,000 )
2018	2018	BRIGHAM YOUNG UNIVERSITY	A-41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	16	12/15/2017	NON-COMPETING CONTINUATION	$313,200
2018	2018	BRIGHAM YOUNG UNIVERSITY	A-41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	16	5/4/2018	NON-COMPETING CONTINUATION	$34,800
														Subtotal = $348,000

Issue Date FY: 2017 ( Subtotal = $348,000 )
2017	2017	BRIGHAM YOUNG UNIVERSITY	A-41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	15	7/3/2017	NON-COMPETING CONTINUATION	$34,800
2017	2017	BRIGHAM YOUNG UNIVERSITY	A-41 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	15	12/15/2016	NON-COMPETING CONTINUATION	$313,200
														Subtotal = $348,000

Issue Date FY: 2016 ( Subtotal = $360,500 )
2016	2016	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	14	12/21/2015	COMPETING CONTINUATION	$360,500
2016	2014	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	13	12/14/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $360,500

Issue Date FY: 2014 ( Subtotal = $367,500 )
2014	2014	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	13	4/16/2014	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2013 ( Subtotal = $356,250 )
2013	2013	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	12	4/24/2013	NON-COMPETING CONTINUATION	$337,500
2013	2013	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	001	12	6/13/2013	NON-COMPETING CONTINUATION	$18,750
														Subtotal = $356,250

Issue Date FY: 2012 ( Subtotal = $375,000 )
2012	2012	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	11	3/22/2012	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2011 ( Subtotal = $375,000 )
2011	2011	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	10	3/28/2011	COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2007 ( Subtotal = $218,483 )
2007	2007	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	9	4/18/2007	NON-COMPETING CONTINUATION	$218,483
														Subtotal = $218,483

Issue Date FY: 2006 ( Subtotal = $219,713 )
2006	2006	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	8	4/21/2006	NON-COMPETING CONTINUATION	$219,713
														Subtotal = $219,713

Issue Date FY: 2005 ( Subtotal = $225,000 )
2005	2005	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	7	4/27/2005	NON-COMPETING CONTINUATION	$225,000
														Subtotal = $225,000

Issue Date FY: 2004 ( Subtotal = $225,000 )
2004	2004	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	6	4/26/2004	COMPETING CONTINUATION	$225,000
														Subtotal = $225,000

Issue Date FY: 2003 ( Subtotal = $172,396 )
2003	2003	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	5		NON-COMPETING CONTINUATION	$172,396
														Subtotal = $172,396

Issue Date FY: 2002 ( Subtotal = $179,697 )
2002	2002	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	4	5/6/2002	NON-COMPETING CONTINUATION	$179,697
														Subtotal = $179,697

Issue Date FY: 2001 ( Subtotal = $177,298 )
2001	2001	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Vision Research	000	3	5/3/2001	NON-COMPETING CONTINUATION	$177,298
														Subtotal = $177,298

Issue Date FY: 2000 ( Subtotal = $172,565 ) (Continued on the next page)
Grand Total All Awards = $5,866,329

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Structural basis for chaperone-dependent folding of beta-propeller proteins essential for vision

Award Number: R01EY012287

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/03/1999

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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