Hypoxia-inducible factors Per/ARNT/Sim domains: structure and function.
Hypoxia-inducible factors (HIFs) are key transcriptional regulators of genes involved in cellular adaptation to reduced oxygen availability through effects on anaerobic metabolism, oxygen delivery, angiogenesis, and cellular survival and proliferation. As such, HIFs contribute to the pathogenesis of diseases in which oxygen availability is compromised, notably ischemia and tumorigenesis. Though tremendous progress has been made in elucidating the mechanisms underlying O(2)-dependent regulation of HIF by Fe(II)- and 2-oxoglutarate-dependent dioxygenases, HIF induction can be uncoupled from these modes of regulation in diseases such as cancer. Consequently, renewed interest has developed in understanding the structure/function relationships of individual P(er)/ARNT/S(im) (PAS) domains that are important for maintaining transcriptionally active HIF complexes, regardless of the manner by which HIF is induced. This review highlights strategies for the biophysical and biochemical characterization of the PAS domains found within both HIF subunits and provides a platform for future efforts to exploit these domains in therapeutic settings.
Scheuermann
Thomas H
TH
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Yang
Jinsong
J
Zhang
Lei
L
Gardner
Kevin H
KH
Bruick
Richard K
RK
D000595:Amino Acid Sequence; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D017930:Genes, Reporter; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D000099162:Endothelial PAS Domain-Containing Protein 1
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011994:Recombinant Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1