Journal article
The impact of solubility and electrostatics on fibril formation by the H3 and H4 histones
Protein science, Vol.20(12), pp.2060-2073
12/2011
Handle:
https://hdl.handle.net/2376/109755
PMCID: PMC3302649
PMID: 21953551
Abstract
The goal of this study was to examine fibril formation by the heterodimeric eukaryotic histones (H2A-H2B and H3-H4) and homodimeric archaeal histones (hMfB and hPyA1). The histone fold dimerization motif is an obligatorily domain-swapped structure comprised of two fused helix:β-loop:helix motifs. Domain swapping has been proposed as a mechanism for the evolution of protein oligomers as well as a means to form precursors in the formation of amyloid-like fibrils. Despite sharing a common fold, the eukaryotic histones of the core nucleosome and archaeal histones fold by kinetic mechanisms of differing complexity with transient population of partially folded monomeric and/or dimeric species. No relationship was apparent between fibrillation propensity and equilibrium stability or population of kinetic intermediates. Only H3 and H4, as isolated monomers and as a heterodimer, readily formed fibrils at room temperature, and this propensity correlates with the significantly lower solubility of these polypeptides. The fibrils were characterized by ThT fluorescence, FTIR, and far-UV CD spectroscopies and electron microscopy. The helical histone fold comprises the protease-resistant core of the fibrils, with little or no protease protection of the poorly structured N-terminal tails. The highly charged tails inhibit fibrillation through electrostatic repulsion. Kinetic studies indicate that H3 and H4 form a co-fibril, with simultaneous incorporation of both histones. The potential impact of H3 and H4 fibrillation on the cytotoxicity of extracellular histones and α-synuclein-mediated neurotoxicity and fibrillation is considered.
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Details
- Title
- The impact of solubility and electrostatics on fibril formation by the H3 and H4 histones
- Creators
- Traci B ToppingLisa M Gloss
- Publication Details
- Protein science, Vol.20(12), pp.2060-2073
- Academic Unit
- Graduate School
- Publisher
- Wiley Subscription Services, Inc., A Wiley Company
- Identifiers
- 99900547228601842
- Language
- English
- Resource Type
- Journal article