1p4q
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Expression of hypoxia-responsive genes is mediated by the heterodimeric | + | Expression of hypoxia-responsive genes is mediated by the heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) in complex with the p300/CREB-binding protein (p300/CBP) transcriptional coactivator. The protein CITED2, which binds p300/CBP, is thought to be a negative regulator of HIF-1 transactivation. We show that the CITED2 transactivation domain (TAD) disrupts a complex of the HIF-1alpha C-terminal TAD (C-TAD) and the cysteine-histidine-rich 1 (CH1) domain of p300/CBP by binding CH1 with high affinity. The high-resolution solution structure of the CITED2 TAD-p300 CH1 complex shows that the CITED2 TAD, like the HIF-1alpha C-TAD, folds on a helical, Zn2+-containing CH1 scaffold. The CITED2 TAD binds a different, more extensive surface of CH1 than does the HIF-1alpha C-TAD. However, a conserved 'LPXL' sequence motif in CITED2 and HIF-1alpha interacts with an overlapping binding site on CH1. Mutation of the LPEL sequence in full-length CITED2 abolishes p300 binding in vivo. These findings reveal that CITED2 regulates HIF-1 by competing for a hot spot on the p300 CH1 domain. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Eck, M | + | [[Category: Eck, M J.]] |
| - | [[Category: France, D | + | [[Category: France, D S.]] |
| - | [[Category: Freedman, S | + | [[Category: Freedman, S J.]] |
| - | [[Category: Kung, A | + | [[Category: Kung, A L.]] |
| - | [[Category: Sun, Z-Y | + | [[Category: Sun, Z-Y J.]] |
[[Category: Wagner, G.]] | [[Category: Wagner, G.]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
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[[Category: protein-protein complex]] | [[Category: protein-protein complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:25:05 2008'' |
Revision as of 12:25, 21 February 2008
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Solution structure of the CITED2 transactivation domain in complex with the p300 CH1 domain
Contents |
Overview
Expression of hypoxia-responsive genes is mediated by the heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) in complex with the p300/CREB-binding protein (p300/CBP) transcriptional coactivator. The protein CITED2, which binds p300/CBP, is thought to be a negative regulator of HIF-1 transactivation. We show that the CITED2 transactivation domain (TAD) disrupts a complex of the HIF-1alpha C-terminal TAD (C-TAD) and the cysteine-histidine-rich 1 (CH1) domain of p300/CBP by binding CH1 with high affinity. The high-resolution solution structure of the CITED2 TAD-p300 CH1 complex shows that the CITED2 TAD, like the HIF-1alpha C-TAD, folds on a helical, Zn2+-containing CH1 scaffold. The CITED2 TAD binds a different, more extensive surface of CH1 than does the HIF-1alpha C-TAD. However, a conserved 'LPXL' sequence motif in CITED2 and HIF-1alpha interacts with an overlapping binding site on CH1. Mutation of the LPEL sequence in full-length CITED2 abolishes p300 binding in vivo. These findings reveal that CITED2 regulates HIF-1 by competing for a hot spot on the p300 CH1 domain.
Disease
Known diseases associated with this structure: Colorectal cancer OMIM:[602700], Rubinstein-Taybi syndrome OMIM:[602700]
About this Structure
1P4Q is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Histone acetyltransferase, with EC number 2.3.1.48 Full crystallographic information is available from OCA.
Reference
Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2., Freedman SJ, Sun ZY, Kung AL, France DS, Wagner G, Eck MJ, Nat Struct Biol. 2003 Jul;10(7):504-12. PMID:12778114
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