| First Author | De Guzman RN | Year | 2004 |
| Journal | J Biol Chem | Volume | 279 |
| Issue | 4 | Pages | 3042-9 |
| PubMed ID | 14594809 | Mgi Jnum | J:240295 |
| Mgi Id | MGI:5882905 | Doi | 10.1074/jbc.M310348200 |
| Citation | De Guzman RN, et al. (2004) Interaction of the TAZ1 domain of the CREB-binding protein with the activation domain of CITED2: regulation by competition between intrinsically unstructured ligands for non-identical binding sites. J Biol Chem 279(4):3042-9 |
| abstractText | The TAZ1 domain of the homologous transcriptional coactivators CREB-binding protein (CBP) and p300 forms a complex with CITED2 (CBP/p300-interacting transactivator with ED-rich tail), inhibiting the activity of the hypoxia inducible factor (HIF-1alpha) and thereby attenuating the cellular response to low tissue oxygen concentration. We report the NMR structure of the CBP TAZ1 domain bound to the activation domain of CIT-ED2. The structure of TAZ1, consisting of four alpha-helices (alpha(1)-alpha(4)) stabilized by three zinc atoms, is very similar in the CITED2 and HIF-1alpha complexes. The activation domain of CITED2 is unstructured when free and folds upon binding, forming a helix (termed alpha(A)) and an extended structure that wraps around TAZ1. The CITED2 alpha(A) helix packs in the TAZ1 alpha(1)/alpha(4) interface, a site that forms weak interactions with the poorly defined aminoterminal alpha-helix of HIF-1alpha. CITED2 and HIF-1alpha both contain a four residue motif, LP(E/Q)L, which binds in the TAZ1 alpha(1)/alpha(2)/alpha(3) junction in each complex. The carboxyl-terminal region of CITED2 forms an extended structure with hydrophobic contacts in the TAZ1 alpha(1)/alpha(3) interface in the site occupied by the HIF-1alpha alpha(B) helix. CITED2 does not bind at all to the TAZ1 site occupied by the HIF-1alpha carboxyl-terminal helix. The HIF-1alpha and CITED2 domains utilize partly overlapping surfaces of TAZ1 to achieve high affinity binding and to compete effectively with each other for interaction with CBP/p300; CITED2 and HIF-1alpha use these binding sites differently to maintain similar binding affinities in order to displace each other in a feedback loop during the hypoxic response. |
