Phosphorylation-induced conformational changes in the retinoblastoma protein inhibit E2F transactivation domain binding.

ABSTRACT: Inactivation of the retinoblastoma protein (Rb) through phosphorylation is an important step in promoting cell cycle progression, and hyperphosphorylated Rb is commonly found in tumors. Rb phosphorylation prevents its association with the E2F transcription factor; however, the molecular basis for complex inhibition has not been established. We identify here the key phosphorylation events and conformational changes that occur in Rb to inhibit the specific association between the E2F transactivation domain (E2F(TD)) and the Rb pocket domain. Calorimetry assays demonstrate that phosphorylation of Rb reduces the affinity of E2F(TD) binding approximately 250-fold and that phosphorylation at Ser(608)/Ser(612) and Thr(356)/Thr(373) is necessary and sufficient for this effect. An NMR assay identif

SUBMITTER: Burke JR 

PROVIDER: S-EPMC2871496 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature