Article | Published:

Structural integration in hypoxia-inducible factors

Nature volume 524, pages 303308 (20 August 2015) | Download Citation

Abstract

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α–ARNT and HIF-1α–ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α–ARNT and HIF-1α–ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

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Accessions

Data deposits

Coordinates and structure factors have been deposited in Protein Data Bank under accession numbers 4ZP4 (HIF-2α–ARNT apo), 4ZQD (HIF-2α–ARNT–0X3), 4ZPH (HIF-2α–ARNT–Proflavine), 4ZPK (HIF-2α–ARNT–DNA) and 4ZPR (HIF-1α–ARNT–DNA).

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Acknowledgements

We thank Y. Zhang and M. Wang for isolation and identification of trypaflavin.

Author information

Affiliations

  1. Metabolic Disease Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA

    • Dalei Wu
    • , Nalini Potluri
    • , Jingping Lu
    •  & Fraydoon Rastinejad
  2. Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA

    • Youngchang Kim

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Contributions

D.W. and F.R. conceived the study; D.W. isolated the proteins, carried out crystallizations and conducted biochemical studies; N.P. produced the expression and mutation constructs; Y.K. and J.L. collected synchrotron diffraction data; D.W., Y.K. and F.R. analysed the data; F.R. and D.W. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Fraydoon Rastinejad.

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    Supplementary Information

    This file contains uncropped scans with size marker indications for Figure 2b.

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https://doi.org/10.1038/nature14883

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