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An order-to-disorder structural switch regulates HIF-1 transcription through S247 phosphorylation in the HIF1α PAS-B domain by Chia-Hung Hsu; Ya-Jyun Chen; Chia-Ning Yang is a Medicine article available to read on EtoBox.

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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 do

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Author

Chia-Hung Hsu; Ya-Jyun Chen; Chia-Ning Yang

Publisher

Elsevier BV

Published

2022

Language

EN

Field

Medicine (Physical Sciences)