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The role of weak multivalent interactions and phase separation in SPOP tumor suppressor function

Award Number: R01GM112846
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: 01/01/2015
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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The role of weak multivalent interactions and phase separation in SPOP tumor suppressor function - SUMMARY Liquid-liquid phase separation (LLPS), i.e. the ability of molecules to condense into liquid-like assemblies, compartmentalizes cells extensively and impacts many fundamental biological processes. Whether LLPS is required for function in cells remains largely unclear. One challenge in answering this question arises from the difficulty in modulating the ability to form condensates without affecting the proteins' function, because assembly and function are often mediated by the same interactions. It is possible that smaller, discrete complexes are able to facilitate the function. We will address this question in enzymatically active condensates of the tumor suppressor speckle-type POZ protein (SPOP). SPOP recruits substrates to a ubiquitin ligase for ubiquitination. We have recently shown that SPOP and substrates undergo LLPS via weak, multivalent interactions, which result in their colocalization in active, membraneless organelles. Prostate cancer mutations blunt the ability of SPOP to phase separate with substrates, leading to their separate localization in cells, to increased substrate levels, and transformation of susceptible cells. We have experience in characterizing multivalent, disordered and phase-separating systems, and have built the necessary in vitro biophysical, biochemical and cell biological approaches and reagents to tackle the above question. In the proposed work, we will first modulate the material properties of condensates to test the requirement of fluidity for effective enzymatic activity. Second, we will test whether designed monovalent substrates, which bind at similar affinities as their multivalent counterparts, can be ubiquitinated effectively in the absence of phase separation. Third, we will make use of cancer mutations that modulate the formation of condensates and discrete complexes in opposite directions to test which of the two are the major players in SPOP function. Forth, we will address the critical question whether the weak interactions that typically mediate LLPS are able to compartmentalize cells specifically. We will use SPOP endometrial cancer mutations, which alter substrate specificity, to identify the strongest motifs responsible for the specificity alteration. The results will provide a conservative measure of specificity-mediating affinities in phase-separating systems. Our rigorous, multidisciplinary studies will significantly advance the knowledge of the structural determinants of specificity in weak SPOP/substrate interactions that drive phase separation, of the necessity of phase separation for SPOP-mediated substrate ubiquitination, and of the biophysical basis for the dysfunction of several SPOP cancer mutations that are distinct from the well-characterized prostate cancer mutations. The expected results will therefore provide conceptual insights into the role of phase separation in biological function. While we use rare cancer-associated mutations mainly as guides towards understanding of normal SPOP function, our work may ultimately help guide target validation for developing therapeutics against SPOP- related cancers.


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 = -$1,500 )
2025	2023	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	9	4/16/2025	NON-COMPETING CONTINUATION	-$1,500
														Subtotal = -$1,500

Issue Date FY: 2023 ( Subtotal = $359,000 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	9	12/2/2022	NON-COMPETING CONTINUATION	$323,100
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	003	9	2/16/2023	NON-COMPETING CONTINUATION	$35,900
2023	2020	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	002	6	2/14/2023	COMPETING CONTINUATION	$84,893
2023	2019	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	5	2/14/2023	NON-COMPETING CONTINUATION	-$84,893
														Subtotal = $359,000

Issue Date FY: 2022 ( Subtotal = $359,000 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	8	8/2/2022	NON-COMPETING CONTINUATION	$35,900
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	8	12/22/2021	NON-COMPETING CONTINUATION	$323,100
														Subtotal = $359,000

Issue Date FY: 2021 ( Subtotal = $359,000 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	7	2/23/2021	NON-COMPETING CONTINUATION	$35,900
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	7	12/8/2020	NON-COMPETING CONTINUATION	$323,100
														Subtotal = $359,000

Issue Date FY: 2020 ( Subtotal = $359,000 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	6	12/11/2019	COMPETING CONTINUATION	$359,000
2020	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	5	5/8/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $359,000

Issue Date FY: 2019 ( Subtotal = $310,984 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	5	12/18/2018	NON-COMPETING CONTINUATION	$310,984
														Subtotal = $310,984

Issue Date FY: 2018 ( Subtotal = $310,984 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	4	11/22/2017	NON-COMPETING CONTINUATION	$279,885
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	4	6/15/2018	NON-COMPETING CONTINUATION	$31,099
														Subtotal = $310,984

Issue Date FY: 2017 ( Subtotal = $310,984 )
2017	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	3	8/11/2017	NON-COMPETING CONTINUATION	$31,099
2017	2017	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	3	12/27/2016	NON-COMPETING CONTINUATION	$279,885
														Subtotal = $310,984

Issue Date FY: 2016 ( Subtotal = $309,685 )
2016	2016	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	001	2	2/22/2016	NON-COMPETING CONTINUATION	$30,969
2016	2016	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	2	11/24/2015	NON-COMPETING CONTINUATION	$278,716
														Subtotal = $309,685

Issue Date FY: 2015 ( Subtotal = $331,247 )
2015	2015	ST JUDE CHILDREN`S RESEARCH HOSPITAL	322 NORTH LAUDERDALE STREET	MEMPHIS	TN	38105	SHELBY	USA	Biomedical Research and Research Training	000	1	12/15/2014	NEW	$331,247
														Subtotal = $331,247

Grand Total All Awards = $3,008,384

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The role of weak multivalent interactions and phase separation in SPOP tumor suppressor function

Award Number: R01GM112846

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: 01/01/2015

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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