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Hypoxia-inducible factor 1 (HIF-1), a transcriptional activator that mediates cellular responses to hypoxic stress, is essential for tumor progression. It is a heterodimer comprising HIF1α and HIF1β, with multiple interfaces among their PAS-A, PAS-B, and bHLH domains. HIF1β is also known as aryl hydrocarbon receptor nuclear translocator (ARNT). 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. 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. 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. 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. 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. Both conformations were also collected in parallel simulations of the unphosphorylated PAS-B domain. Both structures manage to associate with the ARNT PAS-B and HIF1α PAS-A domains; thus, they are adequate for HIF1α-ARNT complex formation. 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. |
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