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Structure and Function of E3 Ligases

Award Number: F31AI197805
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 10/13/2026
PERIOD OF PERFORMANCE END DATE: 10/12/2027

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Structure and Function of E3 Ligases - Abstract Post-translational modification by ubiquitin (Ub) is crucial for various cellular processes, such as DNA repair, signal transduction, and protein degradation. Ubiquitination involves an enzymatic cascade comprising Ub activating enzymes (E1), Ub conjugating enzymes (E2), and Ub ligases (E3). In a process that requires ATP hydrolysis, E1 forms a thioester bond with Ub, E2 recruits Ub from E1, and E3 ligases facilitate Ub conjugation onto substrates. Cullin-RING E3 ligases, such as the Cullin4-RING ubiquitin ligase (CRL4), act as scaffolds bridging E2-Ub and substrates for direct Ub conjugation. SAMHD1, a crucial host restriction enzyme, forms a homotetramer that is catalytically active in hydrolyzing dNTPs, resulting in insufficient dNTP levels for retroviruses to conduct reverse transcription. Intriguingly, one of the hallmarks of HIV-2 involves its adept evasion of host immunity by employing Vpx protein to effectively hijack CRL4 to orchestrate the ubiquitylation and degradation of SAMHD1. Despite the crucial importance, the precise molecular mechanisms by which the CRL4DCAF1 complex is hijacked by Vpx and targets SAMHD1 for ubiquitination remain unknown. We aim to determine the CRL4/DDB1/DCAF1/Vpx/SAMHD1/E2-Ub complex which will reveal the architecture of the complex and conformational changes and contacts that accompany E2 discharge of ubiquitin onto SAMHD1. We will address this in the following Specific Aims. Aim 1 will involve reconstitution, biochemical, and cryo- EM analysis of the key complexes and subcomplexes involved in CRL4-meditated ubiquitination of SAMHD1. In Aim 2, I will leverage the reagents generated in Aim 1 to develop a chemical crosslinking strategy that will trap the complex with the E2 active site and the SAMHD1 target lysine in proximity to each other. We will subject this trapped complex to cryo-EM studies which will reveal the architecture, conformational changes and contacts required for CRL4-meditated ubiquitination of SAMHD1.


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 = $39,874 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	4/13/2026	NEW	$39,874
														Subtotal = $39,874

Grand Total All Awards = $39,874

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Structure and Function of E3 Ligases

Award Number: F31AI197805

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 10/13/2026

PERIOD OF PERFORMANCE END DATE: 10/12/2027

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