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Structural Biology of the Ubiquitin Conjugation System

Award Number: R01GM115568
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: 09/22/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Structural Biology of the Ubiquitin Conjugation System - Project Summary Posttranslational modification of proteins by ubiquitin (Ub) is a regulatory mechanism that controls nearly all aspects eukaryotic cell biology. Ubiquitination alters properties of target proteins such as stability, subcellular localization, intermolecular interactions, and activity and thereby regulates processes such as cell cycle control, DNA repair, signal transduction, and immunity. The relevance of Ub signaling to human health is underscored by the fact that its dysregulation is implicated in pathologies such as cancer, neurological disorders, cardiovascular disease, and immune disorders and that it is a validated target for therapeutic intervention in cancer with FDA-approved medications extending the lives of multiple myeloma patients. Ub signaling requires the sequential interactions and activities of three enzymes, E1, E2, and E3, which act in tandem to conjugate Ub to target proteins. Humans harbor two Ub E1s, Uba1 and Uba6, that catalyze Ub activation and thioester transfer to distinct repertoires of tens of E2s. While Uba1 is fully dedicated to Ub activation, Uba6 is highly unusual in that it is also capable of activating FAT10 (a Ub-like protein involved in mitotic progression and immunity), and subsequently transferring it to a highly Uba6-specific E2, UBE2Z. Maintenance of the integrity of Ub signaling is essential, yet mechanisms underlying Uba6 promiscuity for Ub and FAT10, as well as the molecular rules governing specificity/promiscuity in E1/E2 interactions remain poorly understood. After E1-E2 thioester transfer, E2~Ub intermediates interact with distinct repertoires of hundreds of E3 ligases grouped into three families that catalyze ubiquitination of target proteins as a single molecule or as polymeric chains linked together by specific lysine residues on Ub. Because it is a major determinant of the functional outcome of ubiquitination, control of the type of polyUb chains assembled on substrate proteins is essential and for reactions catalyzed by RING E3s, polyUb chain specificity is largely determined by the E2 with which they function. Despite this fundamental importance, the molecular mechanisms governing specificity in catalysis of most polyUb linkage types remain unknown. Through use of structural, biochemical/biophysical, and cell-based approaches, this proposal aims to discover: 1) the structural basis for substrate recognition and catalytic activities of human Ub E1 enzymes 2) the catalytic mechanism of E1-E2 thioester transfer and molecular rules governing specificity/promiscuity in Ub E1/E2 interactions, and 3) mechanisms by which specific types of polyUb chains are catalyzed by E2/RING E3 pairs. Ub signaling is a target for therapeutic intervention in cancer and other human pathologies and the deeper understanding of how E1, E2, and E3 work together to control essential cellular processes that will result from the proposed studies could provide a platform for the development of novel small molecule therapeutics.


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: 2023 ( Subtotal = $315,257 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	001	9	8/24/2023	NON-COMPETING CONTINUATION	$315,674
2023	2019	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	5	11/21/2022	NON-COMPETING CONTINUATION	-$417
														Subtotal = $315,257

Issue Date FY: 2022 ( Subtotal = $316,091 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	000	8	7/29/2022	NON-COMPETING CONTINUATION	$315,674
2022	2019	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	001	5	9/26/2022	NON-COMPETING CONTINUATION	$417
														Subtotal = $316,091

Issue Date FY: 2021 ( Subtotal = $315,508 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	002	7	7/30/2021	NON-COMPETING CONTINUATION	$315,508
2021	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	001	6	7/3/2021	COMPETING CONTINUATION	$48,827
2021	2019	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	5	7/3/2021	NON-COMPETING CONTINUATION	-$48,827
														Subtotal = $315,508

Issue Date FY: 2020 ( Subtotal = $313,680 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Biomedical Research and Research Training	000	6	7/27/2020	COMPETING CONTINUATION	$313,680
														Subtotal = $313,680

Issue Date FY: 2019 ( Subtotal = $295,263 )
2019	2019	MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	5	7/15/2019	NON-COMPETING CONTINUATION	$295,263
														Subtotal = $295,263

Issue Date FY: 2018 ( Subtotal = $295,263 )
2018	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	4	7/2/2018	NON-COMPETING CONTINUATION	$295,263
														Subtotal = $295,263

Issue Date FY: 2017 ( Subtotal = $295,263 )
2017	2017	MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	3	7/22/2017	NON-COMPETING CONTINUATION	$295,263
														Subtotal = $295,263

Issue Date FY: 2016 ( Subtotal = $295,263 )
2016	2016	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29403	CHARLESTON	USA	Biomedical Research and Research Training	000	2	7/12/2016	NON-COMPETING CONTINUATION	$295,263
														Subtotal = $295,263

Issue Date FY: 2015 ( Subtotal = $295,263 )
2015	2015	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29403	CHARLESTON	USA	Biomedical Research and Research Training	000	1	9/21/2015	NEW	$295,263
														Subtotal = $295,263

Grand Total All Awards = $2,736,851

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Structural Biology of the Ubiquitin Conjugation System

Award Number: R01GM115568

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: 09/22/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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