HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
Ivan
M
M
Dana-Farber Cancer Institute and Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Kondo
K
K
Yang
H
H
Kim
W
W
Valiando
J
J
Ohh
M
M
Salic
A
A
Asara
J M
JM
Lane
W S
WS
Kaelin
W G
WG
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015687:Cell Hypoxia; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D006909:Hydroxyproline / Q000378:metabolism*; D008025:Ligases; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D003676:Deferoxamine; D006909:Hydroxyproline; D008025:Ligases; D010100:Oxygen; D011506:Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human; C018021:cobaltous chloride