We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Structural basis for negative regulation of hypoxia-inducible factor-1a by CITED2.
- Authors
Freedman, Steven J; Sun, Zhen-Yu J; Kung, Andrew L; France, Dennis S; Wagner, Gerhard; Eck, Michael J
- 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-1a 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-1a 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-1a C-TAD. However, a conserved 'LPXL' sequence motif in CITED2 and HIF-1a 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.
- Subjects
GENETIC regulation; GENE expression; TRANSCRIPTION factors; GENES
- Publication
Nature Structural Biology, 2003, Vol 10, Issue 7, p504
- ISSN
1072-8368
- Publication type
Article
- DOI
10.1038/nsb936