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Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.

ABSTRACT: Little is known about how combinations of histone marks are interpreted at the level of nucleosomes. The second PHD finger of human BPTF is known to specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here, we examine how additional heterotypic modifications influence BPTF binding. Using peptide surrogates, three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization. Although the bromodomain displays limited discrimination among the three possible acetyllysines at the peptide level, marked selectivity is observed for only one of these sites, H4K16ac, in combination with H3K4me3 at the mononucleosome level. In support, these two histone marks constitute a unique trans-histone modification pattern that unambiguously resides within a single nucleosomal unit in human cells, and this module colocalizes with these marks in the genome. Together, our data call attention to nucleosomal patterning of covalent marks in dictating critical chromatin associations.

SUBMITTER: Ruthenburg AJ

PROVIDER: S-EPMC3135172 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.

Ruthenburg Alexander J AJ Li Haitao H Milne Thomas A TA Dewell Scott S McGinty Robert K RK Yuen Melanie M Ueberheide Beatrix B Dou Yali Y Muir Tom W TW Patel Dinshaw J DJ Allis C David CD

Cell 20110519 5

Little is known about how combinations of histone marks are interpreted at the level of nucleosomes. The second PHD finger of human BPTF is known to specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here, we examine how additional heterotypic modifications influence BPTF binding. Using peptide surrogates, three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization. Although the bromodomain di ...[more]

PMID: 21596426

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Project description:The targeted delivery of nanoparticle carriers holds tremendous potential to transform the detection and treatment of diseases. A major attribute of nanoparticles is the ability to form multiple bonds with target cells, which greatly improves the adhesion strength. However, the multivalent binding of nanoparticles is still poorly understood, particularly from a dynamic perspective. In previous experimental work, we studied the kinetics of nanoparticle adhesion and found that the rate of detachment decreased over time. Here, we have applied the adhesive dynamics simulation framework to investigate binding dynamics between an antibody-conjugated, 200-nm-diameter sphere and an ICAM-1-coated surface on the scale of individual bonds. We found that nano adhesive dynamics (NAD) simulations could replicate the time-varying nanoparticle detachment behavior that we observed in experiments. As expected, this behavior correlated with a steady increase in mean bond number with time, but this was attributed to bond accumulation only during the first second that nanoparticles were bound. Longer-term increases in bond number instead were manifested from nanoparticle detachment serving as a selection mechanism to eliminate nanoparticles that had randomly been confined to lower bond valencies. Thus, time-dependent nanoparticle detachment reflects an evolution of the remaining nanoparticle population toward higher overall bond valency. We also found that NAD simulations precisely matched experiments whenever mechanical force loads on bonds were high enough to directly induce rupture. These mechanical forces were in excess of 300 pN and primarily arose from the Brownian motion of the nanoparticle, but we also identified a valency-dependent contribution from bonds pulling on each other. In summary, we have achieved excellent kinetic consistency between NAD simulations and experiments, which has revealed new insights into the dynamics and biophysics of multivalent nanoparticle adhesion. In future work, we will leverage the simulation as a design tool for optimizing targeted nanoparticle agents.

Dataset Information

Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.

Publications

Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.

Similar Datasets

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