8E1D

NMR-derived ensemble of the TAZ2 domain of p300 bound to the microphthalmia-associated transcription factor

Summary for 8E1D

• Entry DOI: 10.2210/pdb8e1d/pdb
• NMR Information: BMRB: 31038
• Descriptor: Microphthalmia-associated transcription factor, Histone acetyltransferase p300, ZINC ION (3 entities in total)
• Functional Keywords: taz2, mitf, metal binding protein, transcription-transferase complex, transcription/transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 14024.27

Authors

Langelaan, D.N.,Branch, M. (deposition date: 2022-08-10, release date: 2023-06-21, Last modification date: 2024-05-15)

Primary citation

Brown, A.D.,Vergunst, K.L.,Branch, M.,Blair, C.M.,Dupre, D.J.,Baillie, G.S.,Langelaan, D.N.
Structural basis of CBP/p300 recruitment by the microphthalmia-associated transcription factor.
Biochim Biophys Acta Mol Cell Res, 1870:119520-119520, 2023

PubMed Abstract: 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) and CBP/p300. Using pulldown assays and nuclear magnetic resonance spectroscopy we determined that MITF is intrinsically disordered and binds to the TAZ1 and TAZ2 domains of CBP/p300 with moderate affinity. The solution-state structure of the MITF: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:TAZ2 interaction and is necessary for transcriptional activity of MITF. Peptides that bind to the same surface of TAZ2 as MITF, 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.

PubMed: 37353163
DOI: 10.1016/j.bbamcr.2023.119520

Experimental method

SOLUTION NMR