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.

摘要: The TAZ1 domain of the homologous transcriptional coactivators CREB-binding protein (CBP) and p300 forms a complex with CITED2 (CBP/p300-interacting transactivator ED-rich tail), inhibiting activity hypoxia inducible factor (HIF-1α) thereby attenuating cellular response to low tissue oxygen concentration. We report NMR structure CBP bound activation CIT-ED2. TAZ1, consisting four α-helices (α1-α4) stabilized by three zinc atoms, is very similar in HIF-1α complexes. unstructured when free folds upon binding, forming helix (termed αA) an extended that wraps around TAZ1. αA packs α1/α4 interface, site weak interactions poorly defined aminoterminal α-helix HIF-1α. both contain residue motif, LP(E/Q)L, which binds α1/α2/α3 junction each complex. carboxyl-terminal region hydrophobic contacts α1/α3 interface occupied αB helix. does not bind at all domains utilize partly overlapping surfaces achieve high affinity binding compete effectively other for interaction CBP/p300; use these sites differently maintain affinities order displace feedback loop during hypoxic response.