1P4Q

Solution structure of the CITED2 transactivation domain in complex with the p300 CH1 domain

Summary for 1P4Q

• Entry DOI: 10.2210/pdb1p4q/pdb
• Related: 1L3E
• Descriptor: Cbp/p300-interacting transactivator 2, E1A-associated protein p300, ZINC ION (3 entities in total)
• Functional Keywords: helix, protein-protein complex, transcription-transferase complex, transcription/transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q99967; Cytoplasm: Q09472
• Total number of polymer chains: 2
• Total formula weight: 17421.93

Authors

Freedman, S.J.,Sun, Z.-Y.J.,Kung, A.L.,France, D.S.,Wagner, G.,Eck, M.J. (deposition date: 2003-04-23, release date: 2003-07-01, Last modification date: 2024-10-16)

Primary citation

Freedman, S.J.,Sun, Z.Y.,Kung, A.L.,France, D.S.,Wagner, G.,Eck, M.J.
Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2.
Nat.Struct.Biol., 10:504-512, 2003

PubMed Abstract: 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.

PubMed: 12778114
DOI: 10.1038/nsb936

Experimental method

SOLUTION NMR