Structure and function of E3 ligases
Active Project Grant Awarded Last action
- Award ID
- F31AI197805
- Recipient
-
The University Of Texas Health Science Center At San Antonio UEI C3KXNLTAAY98
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $79,748
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 3% complete
- Originally
- Place of performance
- San Antonio, TX 78229, USA
Award details come from USAspending.gov.
Description
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $39,874 | |
| Amendment | $39,874 | |
| Original award | $0 |
Quick answers
Who received award F31AI197805?
F31AI197805 was awarded to The University Of Texas Health Science Center At San Antonio by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on October 13, 2026.
How much is award F31AI197805 worth?
$79,748 has been obligated on F31AI197805.
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