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How ubiquitin-carrying enzymes contribute to ubiquitin ligase specificity

Award Number: R01GM141409
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: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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How ubiquitin-carrying enzymes contribute to ubiquitin ligase specificity - The reversible control of enzyme activity is one of the cornerstone features enabling life. Cycles of protein phosophorylation and de-phosphorylation have been appreciated for decades to regulate enzymes, and the pharmacological inhibition of protein kinases and phosphatases has furnished a biotech industry intent on treating various human diseases for nearly as long. One major drawback to this strategy is that the enzymes that regulate protein phosphorylation represent perhaps 5 % of the human proteome, such that the vast majority of aberrant proteins responsible for human disease have remained undruggable. More recently, drugs have been invented that induce proximity between a disease-causing protein and an enzyme called a ubiquitin ligase that promotes the destruction of the problematic protein. Indeed, this new drug modality is feeding a billion dollar per year industry push to employ ubiquitin ligases to treat various human diseases including breast and prostate cancers as well as multiple myeloma, to name a few. Most of these efforts have been utilizing a family of enzymes called the Cullin-RING ligases (CRLs). With some 200 members in humans, the CRLs collectively control approximately 20 % of ubiquitin-dependent protein degradation in cells. As such, an appreciation for how these enzymes are regulated is of considerable interest to a wide audience from the scientific community. Similar to the paradigm of protein phosphorylation, the control of CRLs is believed to be determined predominantly through their reversible modification with a protein called NEDD8. And while human CRLs are known to partner with at least 7 additional enzymes, which we refer to as ubiquitin-carrying enzymes (UCEs), that help promote CRL- dependent protein substrate degradation, it also was believed that UCEs act promiscuously towards CRLs which would preclude CRL regulation at the level of CRL-UCE interaction. However, CRL-UCE specificity is strongly implied by the recent structure of an active CRL. Preliminary results here indicate that CRL-UCE specificity endows these pairs with exceptionally rapid rates of ubiquitin transfer and with the capability of producing CRL substrates modified with unique poly-ubiquitin chain architectures, potentially providing an additional layer of control of CRL function beyond neddylation. In consideration of these observations, this application seeks to test the hypothesis that UCEs generally display specificity for CRL-substrate complexes, and that the biological purpose of these specific CRL-UCE pairs is to both enhance the rates of ubiquitin transfer from UCEs to CRL substrates as well as to uniquely code the poly-ubiquitin chain to promote outcomes including protein degradation or localization. The proposed studies will explore an entirely novel area of CRL biology, the specificity of UCEs for CRLs, utilizing proteomic and cell biological assays to complement a powerful, quantitative kinetics platform. These studies will illuminate how CRL activities are regulated and support a new drug modality that harnesses the power of CRLs to degrade disease-causing 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: 2024 ( Subtotal = $353,173 )
2024	2024	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	000	4	2/21/2024	NON-COMPETING CONTINUATION	$317,857
2024	2024	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	001	4	7/12/2024	NON-COMPETING CONTINUATION	$35,316
														Subtotal = $353,173

Issue Date FY: 2023 ( Subtotal = $439,233 )
2023	2023	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	001	3	6/28/2023	SUPPLEMENT FOR EXPANSION	$86,060
2023	2023	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	000	3	3/2/2023	NON-COMPETING CONTINUATION	$353,173
														Subtotal = $439,233

Issue Date FY: 2022 ( Subtotal = $353,173 )
2022	2022	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	001	2	6/23/2022	NON-COMPETING CONTINUATION	$35,321
2022	2022	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	000	2	3/3/2022	NON-COMPETING CONTINUATION	$317,852
														Subtotal = $353,173

Issue Date FY: 2021 ( Subtotal = $460,026 )
2021	2021	BOARD OF REGENTS NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	000	1	4/21/2021	NEW	$460,026
														Subtotal = $460,026

Grand Total All Awards = $1,605,605

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How ubiquitin-carrying enzymes contribute to ubiquitin ligase specificity

Award Number: R01GM141409

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: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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