期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 15, 期 6, 页码 626-633出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1416
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资金
- NCI NIH HHS [R01 CA092088, CA092088, R01 CA095561, R01 CA087658-10, CA095561, R01 CA087658, CA087658] Funding Source: Medline
- NHGRI NIH HHS [R01 HG004508, R01 HG004508-05] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA095561, R01CA092088, R01CA087658] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG004508] Funding Source: NIH RePORTER
The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, alpha(Z), of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.
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