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Dissecting neomorphic functions mediated by mutant-specific structures of SPOP

Award Number: R01CA301513
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/21/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Dissecting neomorphic functions mediated by mutant-specific structures of SPOP - Summary Mutations in the ubiquitin-proteasome system (UPS), including in ubiquitin-ligase components such as VHL, BRCA1, FBW7, APC and SPOP, lead to deregulation of protein levels and can drive tumorigenesis. Therapeutics against such UPS components are therefore promising, but toxic on-target effects on the wild-type protein in normal cells can severely limit tolerated doses and the therapeutic window. Mutant-specific therapeutics could overcome these limitations. Hence, the characterization of cancer mutants that adopt different structures than WT proteins is of importance for making progress in the direction of mutant-specific therapies. Here we propose to capitalize on recent breakthroughs from my laboratory, in which we solved the first structure of full-length SPOP (the Speckle-type POZ protein), which is a substrate receptor of the Cullin3-RING ubiquitin ligase (CRL3) and recruits substrates to the ligase for their ubiquitination and subsequent degradation. SPOP is frequently mutated in prostate, endometrial, and other solid tumors. Our structure of SPOP reports new protein-protein interfaces that have not been observed in previous structures of partial SPOP constructs. These interfaces are lined with mutations whose underlying molecular mechanism was so far not understood because the mutated residues seemed to be solvent exposed. Furthermore, the structures of two SPOP endometrial cancer mutants and other preliminary data show that these activating cancer mutations have effects on the higher-order structure of SPOP that differentiate them decisively from the WT structure: (i) They shift the equilibrium between a linear filament and a circular donut state, the latter of which is likely inactive based on several lines of preliminary data. Or (ii) they radically alter the higher-order assembly structures. We will capitalize on our recent progress and integrate structural characterization with our previously developed biophysical, biochemical and cell biological tools and reagents to answer the following questions: (1) How does self-association into different states, including linear and circular oligomers, regulate SPOP function? (2) Do the structure-altered SPOP mutants function through their altered structural states? (3) And what is the potential of SPOP mutants to form altered quaternary assemblies? The expected structures of donut states and active complexes will be interrogated by mutagenesis and supplemented with functional assays in vitro and in cells to dissect the molecular mechanisms underlying their super-physiological function. We expect to gain decisive insight into the question whether the structurally altered forms are functionally important, with implications for targeting specifically the mutant forms. We will also gain understanding of how higher-order assemblies can drive hyper-morphic or neo-morphic disease phenotypes. Using machine learning models, we will make our results transferable to other cancer-associated proteins whose function is intrinsic to their ability to form higher-order oligomers.


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 = $524,560 )
2026	2026	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	2	5/7/2026	NON-COMPETING CONTINUATION	$524,560
														Subtotal = $524,560

Issue Date FY: 2025 ( Subtotal = $524,560 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	1	9/5/2025	NEW	$0
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	1	5/21/2025	NEW	$524,560
														Subtotal = $524,560

Grand Total All Awards = $1,049,120

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Dissecting neomorphic functions mediated by mutant-specific structures of SPOP

Award Number: R01CA301513

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/21/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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