Structure, dynamics, and stability of the globular domain of human linker histone H1.0 and the role of positive charges
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Structure, dynamics, and stability of the globular domain of human linker histone H1.0 and the role of positive charges. / Martinsen, Jacob H.; Saar, Daniel; Fernandes, Catarina B.; Schuler, Benjamin; Bugge, Katrine; Kragelund, Birthe B.
In: Protein Science, Vol. 31, No. 4, 2022, p. 918-932.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structure, dynamics, and stability of the globular domain of human linker histone H1.0 and the role of positive charges
AU - Martinsen, Jacob H.
AU - Saar, Daniel
AU - Fernandes, Catarina B.
AU - Schuler, Benjamin
AU - Bugge, Katrine
AU - Kragelund, Birthe B.
PY - 2022
Y1 - 2022
N2 - Linker histone H1 (H1) is an abundant chromatin-binding protein that acts as an epigenetic regulator binding to nucleosomes and altering chromatin structures and dynamics. Nonetheless, the mechanistic details of its function remain poorly understood. Recent work suggest that the number and position of charged side chains on the globular domain (GD) of H1 influence chromatin structure and hence gene repression. Here, we solved the solution structure of the unbound GD of human H1.0, revealing that the structure is almost completely unperturbed by complex formation, except for a loop connecting two antiparallel beta-strands. We further quantified the role of the many positive charges of the GD for its structure and conformational stability through the analysis of 11 charge variants. We find that modulating the number of charges has little effect on the structure, but the stability is affected, resulting in a difference in melting temperature of 26 K between GD of net charge +5 versus +13. This result suggests that the large number of positive charges on H1-GDs have evolved for function rather than structure and high stability. The stabilization of the GD upon binding to DNA can thus be expected to have a pronounced electrostatic component, a contribution that is amenable to modulation by posttranslational modifications, especially acetylation and phosphorylation.
AB - Linker histone H1 (H1) is an abundant chromatin-binding protein that acts as an epigenetic regulator binding to nucleosomes and altering chromatin structures and dynamics. Nonetheless, the mechanistic details of its function remain poorly understood. Recent work suggest that the number and position of charged side chains on the globular domain (GD) of H1 influence chromatin structure and hence gene repression. Here, we solved the solution structure of the unbound GD of human H1.0, revealing that the structure is almost completely unperturbed by complex formation, except for a loop connecting two antiparallel beta-strands. We further quantified the role of the many positive charges of the GD for its structure and conformational stability through the analysis of 11 charge variants. We find that modulating the number of charges has little effect on the structure, but the stability is affected, resulting in a difference in melting temperature of 26 K between GD of net charge +5 versus +13. This result suggests that the large number of positive charges on H1-GDs have evolved for function rather than structure and high stability. The stabilization of the GD upon binding to DNA can thus be expected to have a pronounced electrostatic component, a contribution that is amenable to modulation by posttranslational modifications, especially acetylation and phosphorylation.
KW - CD
KW - histone
KW - NMR
KW - nucleosome
KW - protein electrostatics
KW - protein stability
KW - protein structure
KW - CRYSTAL-STRUCTURE
KW - GENE-EXPRESSION
KW - CHROMATIN
KW - BINDING
KW - RECOGNITION
U2 - 10.1002/pro.4281
DO - 10.1002/pro.4281
M3 - Journal article
C2 - 35066947
VL - 31
SP - 918
EP - 932
JO - Protein Science
JF - Protein Science
SN - 0961-8368
IS - 4
ER -
ID: 300152894