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Cellular protein maturation and degradation

Award Number: R01GM086874
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: 04/01/1999
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Cellular protein maturation and degradation - Summary The vast majority of the ~7,000 proteins that traffic through the mammalian secretory are modified by one or more glycans. These alterations include the modifications of Asn (N-linked) and Ser/Thr (O-linked) residues. Carbohydrates appended to proteins can assist with protein folding, quality control and trafficking, or control their activity and function. In this proposal, we will study the mechanism and role of the addition of the hexose epimers of glucose and mannose in the endoplasmic reticulum (ER). Protein maturation is monitored by a quality control process that evaluates the structural integrity of maturing nascent chains, and permits the passage of properly folded proteins. Alternatively, non-native proteins are marked for ER retention so that the defect can be repaired, or if irreparable, targeted for degradation. Calnexin and calreticulin are ER carbohydrate binding molecular chaperones that direct the folding and trafficking of secretory pathway cargo by selectively binding to monoglucosylated side chains on maturing proteins. Therefore, to a large extent the glucosylation state of a glycoprotein controls its flow proteins in the secretory pathway. The glucosylation state is controlled by the UGGT family members UGGT1 and UGGT2 that appear to selectively modify immature or non-native clients to support persistent chaperone binding. These soluble UGGTs transfer glucose from UDP-glucose to maturing cargo in the early secretory pathway. In the first two aims of this proposal, we will test the hypothesis that the UGGTs are central quality control gatekeepers that control the flux of proteins through the ER by examining their specificity and the role of reglucosylation in the cell. The hexose epimer mannose is also added to proteins in the ER. In contrast to reglucosylation, mannosylation involves the transfer of mannose by a membrane embedded transferase from a dolichol- P-precursor directly to Ser/Thr residues to form an O-glycosidic bond. There are two families of putative O-mannosyltransferases that reside in the ER membrane in mammalian cells, the POMTs (POMT1 and 2) and the recently discovered TMTCs (TMTC1-4). Little is known about their mechanisms of action and the function of adding a mannose to maturing proteins in the ER. We have recently found that TMTC3 is involved in the O-mannosylation of E-cadherin and that E-cadherin’s O-mannosylation aids in cell adhesion and neurodevelopment. Mutations in TMTC3 are associated with the neurodevelopment diseases, underscoring the biological significance of this post-translational modification. Specific aim 3 is to understand the mechanism and significance of O-mannosylation in the ER. The long-term goal of this project is to understand the process of hexose addition including the substrate selection and modification steps, and how these post-translational modifications control the trafficking and functions of proteins.


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 = $115,375 )
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	24	7/24/2025	SUPPLEMENT FOR EXPANSION	$115,375
2025	2023	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	24	7/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $115,375

Issue Date FY: 2023 ( Subtotal = $350,026 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	23	5/16/2023	SUPPLEMENT FOR EXPANSION	$10,638
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	24	7/19/2023	NON-COMPETING CONTINUATION	$339,388
														Subtotal = $350,026

Issue Date FY: 2022 ( Subtotal = $349,913 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	23	7/29/2022	NON-COMPETING CONTINUATION	$339,392
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	22	5/27/2022	SUPPLEMENT FOR EXPANSION	$10,521
														Subtotal = $349,913

Issue Date FY: 2021 ( Subtotal = $339,392 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	002	22	8/4/2021	NON-COMPETING CONTINUATION	$339,392
2021	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	21	7/3/2021	COMPETING CONTINUATION	$53,785
2021	2019	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	20	7/3/2021	NON-COMPETING CONTINUATION	-$53,785
														Subtotal = $339,392

Issue Date FY: 2020 ( Subtotal = $339,392 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	21	8/12/2020	COMPETING CONTINUATION	$339,392
2020	2019	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	20	8/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $339,392

Issue Date FY: 2019 ( Subtotal = $324,154 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	20	6/21/2019	NON-COMPETING CONTINUATION	$324,154
														Subtotal = $324,154

Issue Date FY: 2018 ( Subtotal = $324,954 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	19	5/23/2018	NON-COMPETING CONTINUATION	$324,954
														Subtotal = $324,954

Issue Date FY: 2017 ( Subtotal = $325,714 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	70 BUTTERFIELD TERRACE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	002	18	6/15/2017	NON-COMPETING CONTINUATION	$325,714
2017	2016	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	17	12/17/2016	COMPETING CONTINUATION	$55,391
2017	2015	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	16	12/17/2016	NON-COMPETING CONTINUATION	-$55,391
														Subtotal = $325,714

Issue Date FY: 2016 ( Subtotal = $326,439 )
2016	2016	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	17	7/5/2016	COMPETING CONTINUATION	$326,439
2016	2015	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	16	6/29/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $326,439

Issue Date FY: 2015 ( Subtotal = $284,071 )
2015	2015	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	16	6/19/2015	NON-COMPETING CONTINUATION	$284,071
														Subtotal = $284,071

Issue Date FY: 2014 ( Subtotal = $284,269 )
2014	2014	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	15	5/15/2014	NON-COMPETING CONTINUATION	$284,269
														Subtotal = $284,269

Issue Date FY: 2013 ( Subtotal = $274,774 )
2013	2013	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	14	5/28/2013	NON-COMPETING CONTINUATION	$274,774
														Subtotal = $274,774

Issue Date FY: 2012 ( Subtotal = $276,944 )
2012	2012	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	001	13	6/11/2012	COMPETING CONTINUATION	$276,944
2012	2010	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Trans-NIH Recovery Act Research Support	000	12	6/11/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $276,944

Issue Date FY: 2010 ( Subtotal = $267,995 )
2010	2010	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Trans-NIH Recovery Act Research Support	000	12	9/8/2010	NON-COMPETING CONTINUATION	$267,995
														Subtotal = $267,995

Issue Date FY: 2009 ( Subtotal = $309,662 )
2009	2009	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BUILDING	AMHERST	MA	01003	HAMPSHIRE	USA	Trans-NIH Recovery Act Research Support	000	11	9/22/2009	COMPETING CONTINUATION	$309,662
														Subtotal = $309,662

Grand Total All Awards = $4,493,074

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Cellular protein maturation and degradation

Award Number: R01GM086874

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: 04/01/1999

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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