Structural basis of CBP/p300 recruitment by the microphthalmia-associated transcription factor.

Autor: Brown AD; Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada., Vergunst KL; Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada., Branch M; Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada., Blair CM; School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom of Great Britain and Northern Ireland., Dupré DJ; Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada., Baillie GS; School of Cardiovascular & Metabolic Health, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom of Great Britain and Northern Ireland., Langelaan DN; Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada. Electronic address: david.langelaan@dal.ca.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2023 Oct; Vol. 1870 (7), pp. 119520. Date of Electronic Publication: 2023 Jun 21.
DOI: 10.1016/j.bbamcr.2023.119520
Abstrakt: The microphthalmia-associated transcription factor (MITF) is a master regulator of the melanocyte cell lineage. Aberrant MITF activity can lead to multiple malignancies including skin cancer, where it modulates the progression and invasiveness of melanoma. MITF-regulated gene expression requires recruitment of the transcriptional co-regulator CBP/p300, but details of this process are not fully defined. In this study, we investigate the structural and functional interaction between the MITF N-terminal transactivation domain (MITF TAD ) and CBP/p300. Using pulldown assays and nuclear magnetic resonance spectroscopy we determined that MITF TAD is intrinsically disordered and binds to the TAZ1 and TAZ2 domains of CBP/p300 with moderate affinity. The solution-state structure of the MITF TAD :TAZ2 complex reveals that MITF interacts with a hydrophobic surface of TAZ2, while remaining somewhat dynamic. Peptide array and mutagenesis experiments determined that an acidic motif is integral to the MITF TAD :TAZ2 interaction and is necessary for transcriptional activity of MITF. Peptides that bind to the same surface of TAZ2 as MITF TAD , such as the adenoviral protein E1A, are capable of displacing MITF from TAZ2 and inhibiting transactivation. These findings provide insight into co-activator recruitment by MITF that are fundamental to our understanding of MITF targeted gene regulation and melanoma biology.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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