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New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways

Award Number: R01DK039520
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/1995
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways - Project Summary/Abstract Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in a multitude of biological processes and has major ramifications for human health and disease, including illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of immunity. Our studies of the ubiquitin-proteasome system and ubiquitin-dependent N-degron pathways (previously called “N-end rule pathways”) over more than three decades were made possible, to a large extent, by the present grant (DK039520), currently in its 34th year of support. N-degron pathways recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic N-degron pathway, called the Arg/N-degron pathway, targets, in particular, specific unmodified Nt-residues of protein substrates. Another Nt-proteolytic system, called the Pro/N-degron pathway, recognizes, in particular, the Nt-proline (Pro) residue of protein substrates. This DK039520 renewal application stems from our unpublished studies over the last ~2 years, and focuses on the yeast (S. cerevisiae) Pro/N-degron and Arg/N-degron pathways, including the functions of specific aminopeptidases and the recently discovered ability of Ubr1, the E3 of the Arg/N-degron pathway, to target not only N-degrons but also C-degrons. These and related studies, described in Specific Aims of the DK039520 renewal application, will advance the understanding of protein degradation and the universally present (as well as medically significant) N-degron pathways.


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 = $598,988 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	38	6/27/2025	NON-COMPETING CONTINUATION	$598,988
														Subtotal = $598,988

Issue Date FY: 2024 ( Subtotal = $575,028 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	37	6/17/2024	NON-COMPETING CONTINUATION	$575,028
2024	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	34	7/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $575,028

Issue Date FY: 2023 ( Subtotal = $598,988 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	36	7/4/2023	NON-COMPETING CONTINUATION	$598,988
														Subtotal = $598,988

Issue Date FY: 2022 ( Subtotal = $598,988 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	35	3/23/2022	COMPETING CONTINUATION	$598,988
														Subtotal = $598,988

Issue Date FY: 2021 ( Subtotal = $595,650 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	34	6/30/2021	NON-COMPETING CONTINUATION	$595,650
														Subtotal = $595,650

Issue Date FY: 2020 ( Subtotal = $604,650 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	33	6/25/2020	NON-COMPETING CONTINUATION	$604,650
														Subtotal = $604,650

Issue Date FY: 2019 ( Subtotal = $604,650 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	32	6/24/2019	NON-COMPETING CONTINUATION	$604,650
														Subtotal = $604,650

Issue Date FY: 2018 ( Subtotal = $625,650 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	6/18/2018	NON-COMPETING CONTINUATION	$625,650
														Subtotal = $625,650

Issue Date FY: 2017 ( Subtotal = $617,649 )
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	30	7/28/2017	COMPETING CONTINUATION	$617,650
2017	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	6/7/2017	EXTENSION WITH OR WITHOUT FUNDS	-$1
														Subtotal = $617,649

Issue Date FY: 2016 ( Subtotal = $520,669 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	2/25/2016	EXTENSION WITH OR WITHOUT FUNDS	$520,669
														Subtotal = $520,669

Issue Date FY: 2015 ( Subtotal = $526,759 )
2015	2015	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	2/19/2015	NON-COMPETING CONTINUATION	$526,759
														Subtotal = $526,759

Issue Date FY: 2014 ( Subtotal = $538,939 )
2014	2014	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	2/24/2014	NON-COMPETING CONTINUATION	$538,939
														Subtotal = $538,939

Issue Date FY: 2013 ( Subtotal = $550,684 )
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	26	1/25/2013	COMPETING CONTINUATION	$7,687
2013	2013	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	12/31/2012	COMPETING CONTINUATION	$542,997
														Subtotal = $550,684

Issue Date FY: 2012 ( Subtotal = $548,159 )
2012	2012	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	2/29/2012	NON-COMPETING CONTINUATION	$548,159
														Subtotal = $548,159

Issue Date FY: 2011 ( Subtotal = $548,159 )
2011	2011	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	24	5/30/2011	NON-COMPETING CONTINUATION	$34,261
2011	2011	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	2/24/2011	NON-COMPETING CONTINUATION	$513,898
														Subtotal = $548,159

Issue Date FY: 2010 ( Subtotal = $679,543 )
2010	2010	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	2/11/2010	NON-COMPETING CONTINUATION	$651,543
2010	2010	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	000	22	12/18/2009	SUPPLEMENT FOR EXPANSION	$28,000
2010	2010	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Trans-NIH Recovery Act Research Support	002	22	6/7/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $679,543

Issue Date FY: 2009 ( Subtotal = $641,917 )
2009	2009	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	4/23/2009	COMPETING CONTINUATION	$40,827
2009	2009	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	2/24/2009	COMPETING CONTINUATION	$601,090
														Subtotal = $641,917

Grand Total All Awards = $9,975,070

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New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways

Award Number: R01DK039520

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/11/1995

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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