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A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly.
- Source :
-
Nature [Nature] 2013 Apr 18; Vol. 496 (7445), pp. 377-81. Date of Electronic Publication: 2013 Mar 13. - Publication Year :
- 2013
-
Abstract
- A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.
- Subjects :
- Amino Acid Sequence
Animals
Chromobox Protein Homolog 5
Chromosomal Proteins, Non-Histone ultrastructure
Cryoelectron Microscopy
Gene Silencing
Heterochromatin chemistry
Heterochromatin ultrastructure
Histones chemistry
Histones metabolism
Methylation
Models, Molecular
Molecular Sequence Data
Nucleosomes chemistry
Nucleosomes genetics
Nucleosomes metabolism
Nucleosomes ultrastructure
Protein Structure, Tertiary
Schizosaccharomyces genetics
Schizosaccharomyces pombe Proteins antagonists & inhibitors
Schizosaccharomyces pombe Proteins ultrastructure
Xenopus laevis
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone antagonists & inhibitors
Chromosomal Proteins, Non-Histone chemistry
Chromosomal Proteins, Non-Histone metabolism
Heterochromatin metabolism
Schizosaccharomyces metabolism
Schizosaccharomyces pombe Proteins chemistry
Schizosaccharomyces pombe Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 496
- Issue :
- 7445
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 23485968
- Full Text :
- https://doi.org/10.1038/nature12032