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PMID: 11959990 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 8 ·2002-04-16 ·Pages 5367-72

Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ

Abstract

Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators. We report the solution structure of the cysteine/histidine-rich 1 (CH1) domain of p300 bound to the C-terminal transactivation domain of HIF-1 alpha. CH1 has a triangular geometry composed of four alpha-helices with three intervening Zn(2+)-coordinating centers. CH1 serves as a scaffold for folding of the HIF-1 alpha C-terminal transactivation domain, which forms a vise-like clamp on the CH1 domain that is stabilized by extensive hydrophobic and polar interactions. The structure reveals the mechanism of specific recognition of p300 by HIF-1 alpha, and shows how HIF-1 alpha transactivation is regulated by asparagine hydroxylation.

MeSH Terms
Amino Acid Sequence Animals Asparagine/chemistry Escherichia coli/metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Nuclear Proteins/chemistry Protein Binding Protein Conformation Protein Folding Protein Structure, Secondary Protein Structure, Tertiary Sequence Homology, Amino Acid Trans-Activators/chemistry Transcription Factors/chemistry,metabolism Transcriptional Activation Zinc/chemistry
Chemicals
HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Trans-Activators Transcription Factors Asparagine Zinc
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Freedman Steven J
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Sun Zhen-Yu J
Poy Florence
Kung Andrew L
Livingston David M
Wagner Gerhard
Eck Michael J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.082117899
Published
2002-04-16
Pages
5367-72
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC122775
Subset
IM
Grants
NHLBI NIH HHS · K08 HL · United States
Databases
PDB
1L3E
External Links
PubMed source DOI: 10.1073/pnas.082117899 PMC Full Text View journal details
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