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제114회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Structural basis for regulation of tumor suppressor protein p53 with CBP/p300 and MDM2 interaction

2014년 8월 28일 16시 53분 58초
BIO.O-1 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
금 10시 : 00분
생명화학 - Oral Presentation of Young Biochemists
저자 및
전남대학교 화학과, Korea
The activity and stability of the tumor suppressor p53 are regulated by interactions with key cellular proteins such as MDM2 and CBP/p300. The transactivation domain (TAD) of p53 contains two subdomains (AD1 and AD2) and interacts directly with the N-terminal domain of MDM2 and with several domains of CBP/p300. Using NMR spectroscopy and other biophysical methodologies, we have dissected the binding interactions between the TAD of p53, the TAZ1, TAZ2, KIX, and nuclear receptor coactivator binding domain (NCBD) of CBP, and the p53-binding domain of HDM2 (the human homolog of MDM2). The p53 TAD can bind simultaneously to HDM2 (through AD1) and to any one of the CBP domains (through AD2) to form a ternary complex. The NMR structure of the full-length p53 TAD in complex with NCBD of CBP indicate that the p53 TAD and NCBD are intrinsically disordered and fold synergistically upon binding, which provides the first insights into simultaneous binding of the AD1 and AD2 motifs to a target protein. The transcriptional activity of p53 is regulated by a cascade of posttranslational modifications. We investigated the role of single site and multiple site phosphorylation of the p53 TAD in mediating its interaction with CBP and with HDM2. Phosphorylation at Thr18 functions as an on/off switch to regulate binding to the N-terminal domain of HDM2. In contrast, binding to CBP is modulated by the extent of p53 phosphorylation; addition of successive phosphoryl groups enhances the affinity for the TAZ1, TAZ2, and KIX domains of CBP in an additive manner. Activation of p53-dependent transcriptional pathways requires that p53 compete with numerous cellular transcription factors for binding to limiting amounts of CBP/p300. Multisite phosphorylation represents a mechanism for a graded p53 response, with each successive phosphorylation event resulting in increasingly efficient recruitment of CBP/p300 to p53-regulated transcriptional programs, in the face of competition from cellular transcription factors. Multisite phosphorylation thus acts as a rheostat to enhance binding to CBP/p300 and provides a plausible mechanistic explanation for the gradually increasing p53 response observed following prolonged or severe genotoxic stress.