Projects per year
Abstract
The plant homeodomain (PHD) fingers are amongst the largest family of epigenetic domains, first characterized as readers of methylated H3K4. Readout of histone posttranslational modifications by PHDs has been the subject of intense investigation, however less is known about the recognition of secondary structure features within histone tail itself. We solved the crystal structure of the PHD finger of the bromodomain adjacent to zinc finger 2A (BAZ2A, also known as TIP5) in complex with unmodified N-terminal histone H3 tail. The peptide is bound in a helical folded-back conformation after K4, induced by an acidic patch on the protein surface that prevents peptide binding in an extended conformation. Structural bioinformatics analyses identify a conserved Asp/Glu residue that we name “acidic wall”, found to be mutually exclusive with the conserved Trp for K4Me recognition. Neutralization or inversion of the charges at the acidic wall patch in BAZ2A, and homologous BAZ2B, weakened H3 binding. We identify simple mutations on H3 that strikingly enhance or reduce binding, as a result of their stabilization or de-stabilization of H3 helicity. Our work unravels the structural basis for binding of helical H3 tail by PHD fingers, and suggests that molecular recognition of secondary structure motifs within histone tails could represent an additional layer of regulation in epigenetic processes.
Original language | English |
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Pages (from-to) | 1633-1651 |
Number of pages | 19 |
Journal | Biochemical Journal |
Volume | 474 |
Issue number | 10 |
Early online date | 24 Mar 2017 |
DOIs | |
Publication status | Published - 4 May 2017 |
Keywords
- epigenetics
- PHD finger
- reader domains
- protein-protein interaction
- histone binding
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Dive into the research topics of 'Structural Basis of Molecular Recognition of Helical Histone H3 Tail by PHD Finger Domains'. Together they form a unique fingerprint.Projects
- 3 Finished
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DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/13 → 30/04/18
Project: Research
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Dissecting and Exploiting Molecular Recognition at Protein-Protein Interfaces (David Phillips Fellowship)
Ciulli, A. (Investigator)
Biotechnology and Biological Sciences Research Council
8/04/13 → 7/07/15
Project: Research
Student theses
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Structural studies of paired PHD finger-bromodomain chromatin-binding modules: targeting epigenetic readers with chemical probes
Amato, A. (Author), Ciulli, A. (Supervisor), 2018Student thesis: Doctoral Thesis › Doctor of Philosophy
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Profiles
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Ciulli, Alessio
- Centre for Targeted Protein Degradation - Professor of Chemical and Structural Biology
Person: Academic