Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases

Rasheduzzaman Chowdhury, Michael A. McDonough, Jasmin Mecinović, Christoph Loenarz, Emily Flashman, Kirsty S. Hewitson, Carmen Domene, Christopher J. Schofield*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The oxygen-dependent hydroxylation of proline residues in the α subunit of hypoxia-inducible transcription factor (HIFα) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFα increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1α. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.

OriginalsprogEngelsk
TidsskriftStructure
Vol/bind17
Udgave nummer7
Sider (fra-til)981-989
Antal sider9
ISSN0969-2126
DOI
StatusUdgivet - 15. jul. 2009
Udgivet eksterntJa

Fingeraftryk

Hydroxylation
Oxygen
Proteasome Endopeptidase Complex
Ubiquitin
Catalytic Domain
Enzymes
Proteins

Citer dette

Chowdhury, R., McDonough, M. A., Mecinović, J., Loenarz, C., Flashman, E., Hewitson, K. S., ... Schofield, C. J. (2009). Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases. Structure, 17(7), 981-989. https://doi.org/10.1016/j.str.2009.06.002
Chowdhury, Rasheduzzaman ; McDonough, Michael A. ; Mecinović, Jasmin ; Loenarz, Christoph ; Flashman, Emily ; Hewitson, Kirsty S. ; Domene, Carmen ; Schofield, Christopher J. / Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases. I: Structure. 2009 ; Bind 17, Nr. 7. s. 981-989.
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abstract = "The oxygen-dependent hydroxylation of proline residues in the α subunit of hypoxia-inducible transcription factor (HIFα) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFα increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1α. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.",
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Chowdhury, R, McDonough, MA, Mecinović, J, Loenarz, C, Flashman, E, Hewitson, KS, Domene, C & Schofield, CJ 2009, 'Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases', Structure, bind 17, nr. 7, s. 981-989. https://doi.org/10.1016/j.str.2009.06.002

Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases. / Chowdhury, Rasheduzzaman; McDonough, Michael A.; Mecinović, Jasmin; Loenarz, Christoph; Flashman, Emily; Hewitson, Kirsty S.; Domene, Carmen; Schofield, Christopher J.

I: Structure, Bind 17, Nr. 7, 15.07.2009, s. 981-989.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases

AU - Chowdhury, Rasheduzzaman

AU - McDonough, Michael A.

AU - Mecinović, Jasmin

AU - Loenarz, Christoph

AU - Flashman, Emily

AU - Hewitson, Kirsty S.

AU - Domene, Carmen

AU - Schofield, Christopher J.

PY - 2009/7/15

Y1 - 2009/7/15

N2 - The oxygen-dependent hydroxylation of proline residues in the α subunit of hypoxia-inducible transcription factor (HIFα) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFα increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1α. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.

AB - The oxygen-dependent hydroxylation of proline residues in the α subunit of hypoxia-inducible transcription factor (HIFα) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFα increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1α. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.

KW - PROTEINS

KW - SIGNALLING

UR - http://www.scopus.com/inward/record.url?scp=67649980040&partnerID=8YFLogxK

U2 - 10.1016/j.str.2009.06.002

DO - 10.1016/j.str.2009.06.002

M3 - Journal article

VL - 17

SP - 981

EP - 989

JO - Structure

JF - Structure

SN - 0969-2126

IS - 7

ER -