PMID- 12778114
OWN - NLM
STAT- MEDLINE
DCOM- 20030801
LR  - 20061115
IS  - 1072-8368 (Print)
IS  - 1072-8368 (Linking)
VI  - 10
IP  - 7
DP  - 2003 Jul
TI  - Structural basis for negative regulation of hypoxia-inducible factor-1alpha by 
      CITED2.
PG  - 504-12
AB  - 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.
FAU - Freedman, Steven J
AU  - Freedman SJ
AD  - Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, 41 
      Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
FAU - Sun, Zhen-Yu J
AU  - Sun ZY
FAU - Kung, Andrew L
AU  - Kung AL
FAU - France, Dennis S
AU  - France DS
FAU - Wagner, Gerhard
AU  - Wagner G
FAU - Eck, Michael J
AU  - Eck MJ
LA  - eng
SI  - PDB/1P4Q
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Struct Biol
JT  - Nature structural biology
JID - 9421566
RN  - 0 (CITED2 protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Repressor Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
SB  - IM
CIN - Nat Struct Biol. 2003 Jul;10(7):501-3. PMID: 12825087
MH  - Amino Acid Motifs
MH  - Amino Acid Sequence
MH  - Animals
MH  - Circular Dichroism
MH  - *DNA-Binding Proteins
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Protein Binding
MH  - Protein Conformation
MH  - *Repressor Proteins
MH  - Sequence Homology, Amino Acid
MH  - Trans-Activators/metabolism/*physiology
MH  - Transcription Factors/*chemistry/metabolism/*physiology
EDAT- 2003/06/05 05:00
MHDA- 2003/08/02 05:00
CRDT- 2003/06/05 05:00
PHST- 2003/03/03 00:00 [received]
PHST- 2003/05/07 00:00 [accepted]
PHST- 2003/06/05 05:00 [pubmed]
PHST- 2003/08/02 05:00 [medline]
PHST- 2003/06/05 05:00 [entrez]
AID - nsb936 [pii]
AID - 10.1038/nsb936 [doi]
PST - ppublish
SO  - Nat Struct Biol. 2003 Jul;10(7):504-12. doi: 10.1038/nsb936.