PMID: 36027865 RLIMS-P 1 eFIP 0 miRTex 0 eGARD 0 Issue Report
Title
| 1. | An order-to-disorder structural switch regulates HIF-1 transcription through S247 phosphorylation in the HIF1α PAS-B domain. |
Abstract
| 2. | Hypoxia-inducible factor 1 (HIF-1), a transcriptional activator that mediates cellular responses to hypoxic stress, is essential for tumor progression. |
| 3. | It is a heterodimer comprising HIF1α and HIF1β, with multiple interfaces among their PAS-A, PAS-B, and bHLH domains. |
| 4. | HIF1β is also known as aryl hydrocarbon receptor nuclear translocator (ARNT). |
| 5. | Casein kinase 1δ-dependent phosphorylation of the solvent-front residue S247 on the HIF1α PAS-B domain interrupts HIF1α-ARNT complex formation and reduces HIF-1 transcription activity. |
| 6. | However, S247 is involved in neither HIF1α-ARNT complex formation nor stabilization of the relative orientation between the HIF1α PAS-A and PAS-B domains. |
| 7. | To uncover the underlying allosteric mechanism, we conducted Gaussian accelerated molecular dynamics simulations and identified two distinct conformations of the pS247-carrying HIF1α PAS-B domain: H291-in and H291-out. |
| 8. | The H291-in structure can associate with the HIF1α PAS-A domain and form a V-shaped pouch to accommodate the ARNT PAS-A domain, but it cannot associate with the ARNT PAS-B domain. |
| 9. | By contrast, the H291-out structure can bind to the ARNT PAS-B domain, but its association with the HIF1α PAS-A domain leads to an unsuitable relative orientation to accommodate the ARNT PAS-A domain. |
| 10. | Both conformations were also collected in parallel simulations of the unphosphorylated PAS-B domain. |
| 11. | Both structures manage to associate with the ARNT PAS-B and HIF1α PAS-A domains; thus, they are adequate for HIF1α-ARNT complex formation. |
| 12. | The domain-domain contact pattern in a phosphorylated variant is shuffled by an order-to-disorder structural switch, triggered by the newly formed K251-pS247 interaction. |
Loading...
Loading data
Legend: SUBSTRATE KINASE INTERACTANT SITE GENE MIRNA ANOMALY EXPRESSION DISEASE OUTCOME/RESPONSE SR_DRUG DRUG CELL TRIGGER Normalized
Tool: RLIMS-P
| PTM enzyme | Substrate | Site | Sentence |
|---|---|---|---|
| HIF1α (Q16665) | Ser-247 | 1, 5 |