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Solution structure and dynamics of polyubiquitin chains

Award Number: R01GM065334
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: 03/01/2002
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Solution structure and dynamics of polyubiquitin chains - Project Summary This work will characterize the solution structure, dynamics, and interactions of polyubiquitin (polyUb) chains, which function as signaling molecules in the regulation of a host of cellular processes, ranging from progression through the cell cycle, to transcriptional activation, antigen processing and vesicular trafficking of proteins. Conjugation of substrates to polyUb chains of different linkage types commits the target protein to distinct fates in the cell. In particular, Lys48-linked polyUb acts as a universal signal in the ubiquitin- proteasome proteolytic pathway, the principal regulatory mechanism for the turnover of short-lived proteins that influences a variety of vital cellular events. Understanding how polyUb chains are recognized by the 26S proteasome and other downstream effector molecules is central to our understanding of the mechanisms of regulation. Despite an increasing wealth of information on the cellular processes regulated by polyubiquitination and the identification of numerous ubiquitin-binding proteins that tie the polyUb signal to downstream events, the molecular basis of diversity in ubiquitin-mediated signaling remains unclear. The mechanisms underlying the ability of different polyUb chains to signal for distinct outcomes remain to be elucidated before the origin of specificity in polyUb signaling is understood. Obtaining such information is absolutely necessary in order to develop a molecular understanding of how different polyUb chains are able to act as specific molecular signals. The objective of the proposed work is to characterize the structure and recognition properties of various types of polyUb chains, in order to understand at a molecular level the structural basis for ubiquitin's ability to serve as a versatile yet specific cellular signal. These studies will focus on the so-called non-canonical ubiquitin chains: linked via lysines other than Lys48 or Lys63 (e.g., Lys6, Lys27) and chains containing heterogeneous linkages (e.g., Lys11 & Lys48), branched and unbranched, and the mechanisms of selective recognition of these chains by dedicated receptors from the DNA repair or proteasomal degradation pathways. We will also determine the conformations of the canonical, Lys48-linked tetraUb chains in solution in order to gain insights into the mechanisms of their recognition by cellular receptors. Finally, these studies will characterize the interactions and determine the structures of polyUb complexes with the recently designed macrocyclic peptides that bind polyUb chains with high affinity and linkage specificity, in order to facilitate further development and optimization of this entirely novel class of modulators and potential therapeutics for ubiquitin-mediated signaling pathways. We will use modern NMR approaches in combination with small-angle X-ray and neutron scattering (SAXS, SANS) and other biophysical techniques in order to determine the three-dimensional structures and conformational ensembles of polyUb chains in solution and characterize their binding preferences and complexes with receptors.


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: 2026 ( Subtotal = $336,028 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	20	5/27/2026	NON-COMPETING CONTINUATION	$336,028
														Subtotal = $336,028

Issue Date FY: 2025 ( Subtotal = $336,028 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	19	9/3/2025	NON-COMPETING CONTINUATION	$336,028
2025	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	17	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $336,028

Issue Date FY: 2024 ( Subtotal = $350,028 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	002	18	6/13/2024	COMPETING CONTINUATION	$350,028
2024	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	17	6/5/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	17	6/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $350,028

Issue Date FY: 2022 ( Subtotal = $412,610 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	17	7/28/2022	NON-COMPETING CONTINUATION	$323,603
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	17	9/16/2022	SUPPLEMENT FOR EXPANSION	$89,007
														Subtotal = $412,610

Issue Date FY: 2021 ( Subtotal = $323,603 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	16	7/23/2021	NON-COMPETING CONTINUATION	$323,603
														Subtotal = $323,603

Issue Date FY: 2020 ( Subtotal = $543,434 )
2020	2020	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	15	7/29/2020	SUPPLEMENT FOR EXPANSION	$219,831
2020	2020	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	15	7/28/2020	NON-COMPETING CONTINUATION	$323,603
														Subtotal = $543,434

Issue Date FY: 2019 ( Subtotal = $350,317 )
2019	2019	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	14	9/11/2019	COMPETING CONTINUATION	$350,317
														Subtotal = $350,317

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	13	4/7/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $295,195 )
2015	2015	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	13	2/10/2015	NON-COMPETING CONTINUATION	$29,520
2015	2015	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	13	11/18/2014	NON-COMPETING CONTINUATION	$265,675
														Subtotal = $295,195

Issue Date FY: 2014 ( Subtotal = $295,195 )
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	12	3/11/2014	NON-COMPETING CONTINUATION	$29,519
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	12	11/22/2013	NON-COMPETING CONTINUATION	$265,676
														Subtotal = $295,195

Issue Date FY: 2013 ( Subtotal = $284,863 )
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	11	6/10/2013	NON-COMPETING CONTINUATION	$19,187
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	11	11/30/2012	NON-COMPETING CONTINUATION	$265,676
														Subtotal = $284,863

Issue Date FY: 2012 ( Subtotal = $295,195 )
2012	2012	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	10	12/1/2011	COMPETING CONTINUATION	$295,195
														Subtotal = $295,195

Issue Date FY: 2010 ( Subtotal = $257,276 )
2010	2010	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	9	2/22/2010	NON-COMPETING CONTINUATION	$257,276
														Subtotal = $257,276

Issue Date FY: 2009 ( Subtotal = $492,475 )
2009	2009	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	8	6/8/2009	NON-COMPETING CONTINUATION	$25,987
2009	2009	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	8	2/5/2009	NON-COMPETING CONTINUATION	$233,888
2009	2009	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Trans-NIH Recovery Act Research Support	002	8	9/28/2009	SUPPLEMENT FOR EXPANSION	$232,600
														Subtotal = $492,475

Issue Date FY: 2008 ( Subtotal = $259,875 )
2008	2008	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	7	3/12/2008	NON-COMPETING CONTINUATION	$259,875
														Subtotal = $259,875

Issue Date FY: 2007 ( Subtotal = $259,875 )
2007	2007	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	6	2/26/2007	COMPETING CONTINUATION	$259,875
														Subtotal = $259,875

Issue Date FY: 2006 ( Subtotal = $215,157 )
2006	2006	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	5	2/21/2006	NON-COMPETING CONTINUATION	$215,157
														Subtotal = $215,157

Issue Date FY: 2005 ( Subtotal = $220,335 )
2005	2005	UNIVERSITY OF MARYLAND	1410 SERVICE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	4	3/1/2005	NON-COMPETING CONTINUATION	$220,335
														Subtotal = $220,335

Issue Date FY: 2004 ( Subtotal = $220,335 )
2004	2004	UNIVERSITY OF MARYLAND	1410 SERVICE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	3	2/23/2004	NON-COMPETING CONTINUATION	$220,335
														Subtotal = $220,335

Issue Date FY: 2003 ( Subtotal = $220,335 )
2003	2003	UNIVERSITY OF MARYLAND	1410 SERVICE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Cell Biology and Biophysics Research	000	2		NON-COMPETING CONTINUATION	$220,335
														Subtotal = $220,335

Grand Total All Awards = $6,188,494

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Solution structure and dynamics of polyubiquitin chains

Award Number: R01GM065334

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: 03/01/2002

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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