A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding
Abstract
N-terminal histone tails are subject to many posttranslational modifications that are recognized by and interact with designated reader domains in histone-binding proteins. BROMO domain adjacent to zinc finger 2B (BAZ2B) is a multidomain histone-binding protein that contains two histone reader modules, a plant homeodomain (PHD) and a bromodomain (BRD), linked by a largely disordered linker. Although previous studies have reported specificity of the PHD domain for the unmodified N terminus of histone H3 and of the BRD domain for H3 acetylated at Lys 14 (H3K14ac), the exact mode of H3 binding by BAZ2B and its regulation are underexplored. Here, using isothermal titration calorimetry and NMR spectroscopy, we report that acidic residues in the BAZ2B PHD domain are essential for H3 binding and that BAZ2B PHD–BRD establishes a polyvalent interaction with H3K14ac. Furthermore, we provide evidence that the disordered interdomain linker modulates the histone-binding affinity by interacting with the PHD domain. In particular, lysine-rich stretches in the linker, which resemble the positively charged N terminus of histone H3, reduce the binding affinity of the PHD finger toward the histone substrate. Phosphorylation, acetylation, or poly(ADP-ribosyl)ation of the linker residues may therefore act as a cellular mechanism to transiently tune BAZ2B histone-binding affinity. Our findings further support the concept of interdomain linkers serving a dual role in substrate binding by appropriately positioning the adjacent domains and by electrostatically modulating substrate binding. Moreover, inhibition of histone binding by a histone-mimicking interdomain linker represents another example of regulation of protein–protein interactions by intramolecular mimicry.
Related
- KMT2A modulates the epigenetic landscape of rDNA by facilitating the recruitment of histone lysine acetyltransferase PCAF to the rDNA locus.
- Multivalent Adhesive Probe Atomic Force Microscopy (MAPA) for accessing dispersive adhesion of cells and biosurfaces.
- Multivalent Surface Search Dynamics Shape Bacteriophage Adsorption Efficiency: A Stochastic Model of Tail Fiber Optimization
- Programmable DNA-peptide nanostructures for multivalent regulation of intracellular signalling
- Multivalent Scaffolding by XIST E-Repeats Tunes RNA Binding Protein Cooperativity and Lowers the Phase Separation Threshold
BibTeX
@article{kostrhon2026histonemimicking,
title = {{A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding}},
author = {Sebastian Kostrhon and Georg Kontaxis and Tanja Kaufmann and Erika Schirghuber and Stefan Kubicek and Robert Konrat and Dea Slade},
journal = {Journal of Biological Chemistry},
year = {2026},
month = oct,
doi = {10.1074/jbc.m117.801464},
url = {https://hal.science/hal-05787720v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding
AU - Sebastian Kostrhon
AU - Georg Kontaxis
AU - Tanja Kaufmann
AU - Erika Schirghuber
AU - Stefan Kubicek
AU - Robert Konrat
AU - Dea Slade
PY - 2026
DA - 2026/10/08
JO - Journal of Biological Chemistry
DO - 10.1074/jbc.m117.801464
UR - https://hal.science/hal-05787720v1
AB - N-terminal histone tails are subject to many posttranslational modifications that are recognized by and interact with designated reader domains in histone-binding proteins. BROMO domain adjacent to zinc finger 2B (BAZ2B) is a multidomain histone-binding protein that contains two histone reader modules, a plant homeodomain (PHD) and a bromodomain (BRD), linked by a largely disordered linker. Although previous studies have reported specificity of the PHD domain for the unmodified N terminus of histone H3 and of the BRD domain for H3 acetylated at Lys 14 (H3K14ac), the exact mode of H3 binding by BAZ2B and its regulation are underexplored. Here, using isothermal titration calorimetry and NMR spectroscopy, we report that acidic residues in the BAZ2B PHD domain are essential for H3 binding and that BAZ2B PHD–BRD establishes a polyvalent interaction with H3K14ac. Furthermore, we provide evidence that the disordered interdomain linker modulates the histone-binding affinity by interacting with the PHD domain. In particular, lysine-rich stretches in the linker, which resemble the positively charged N terminus of histone H3, reduce the binding affinity of the PHD finger toward the histone substrate. Phosphorylation, acetylation, or poly(ADP-ribosyl)ation of the linker residues may therefore act as a cellular mechanism to transiently tune BAZ2B histone-binding affinity. Our findings further support the concept of interdomain linkers serving a dual role in substrate binding by appropriately positioning the adjacent domains and by electrostatically modulating substrate binding. Moreover, inhibition of histone binding by a histone-mimicking interdomain linker represents another example of regulation of protein–protein interactions by intramolecular mimicry.
SN - 0021-9258
SN - 1083-351X
ER -