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 Nunez; Christopher J. Schofield

doi:10.1016/j.str.2009.06.002

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 Nunez
, Christopher J. Schofield

Department of Chemistry

University of Oxford

Research output: Contribution to journal › Article › peer-review

216 Citations (SciVal)

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.

Original language	English
Pages (from-to)	981-989
Number of pages	9
Journal	Structure
Volume	17
Issue number	7
Early online date	14 Jul 2009
DOIs	https://doi.org/10.1016/j.str.2009.06.002
Publication status	Published - 15 Jul 2009

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Anoxia, Binding Sites, Catalysis, Catalytic Domain, Crystallography, X-Ray, Humans, Hydroxylation, Hydroxyproline, Hypoxia-Inducible Factor 1, Ketoglutaric Acids, Models, Molecular, Oxygen, Procollagen-Proline Dioxygenase, Proline, Proteasome Endopeptidase Complex, Protein Binding, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Signal Transduction, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein

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title = "Structural Basis for Binding of Hypoxia-Inducible Factor to the Oxygen-Sensing Prolyl Hydroxylases",

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.",

keywords = "Anoxia, Binding Sites, Catalysis, Catalytic Domain, Crystallography, X-Ray, Humans, Hydroxylation, Hydroxyproline, Hypoxia-Inducible Factor 1, Ketoglutaric Acids, Models, Molecular, Oxygen, Procollagen-Proline Dioxygenase, Proline, Proteasome Endopeptidase Complex, Protein Binding, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Signal Transduction, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein",

author = "Rasheduzzaman Chowdhury and McDonough, \{Michael A.\} and Jasmin Mecinovi{\'c} and Christoph Loenarz and Emily Flashman and Hewitson, \{Kirsty S\} and \{Domene Nunez\}, Carmen and Schofield, \{Christopher J.\}",

year = "2009",

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doi = "10.1016/j.str.2009.06.002",

language = "English",

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journal = "Structure",

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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 Nunez, 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 - Anoxia, Binding Sites, Catalysis, Catalytic Domain, Crystallography, X-Ray, Humans, Hydroxylation, Hydroxyproline, Hypoxia-Inducible Factor 1, Ketoglutaric Acids, Models, Molecular, Oxygen, Procollagen-Proline Dioxygenase, Proline, Proteasome Endopeptidas

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DO - 10.1016/j.str.2009.06.002

M3 - Article

SN - 0969-2126

VL - 17

SP - 981

EP - 989

JO - Structure

JF - Structure

IS - 7

ER -

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

Abstract

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Keywords

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