Genes Dev.-2019-Leopold-gad.320440.118.pdf (4.92 MB)
Transcriptional gene silencing requires dedicated interaction between HP1 protein Chp2 and chromatin remodeler Mit1.
journal contributionposted on 2019-06-14, 12:47 authored by Karoline Leopold, Alessandro Stirpe, Thomas Schalch
Heterochromatin protein 1 (HP1) proteins are key factors of eukaryotic heterochromatin that coordinate chromatin compaction and transcriptional gene silencing. Through their multivalency they act as adaptors between histone H3 Lys9 di/trimethyl marks in chromatin and effector complexes that bind to the HP1 chromoshadow domain. Most organisms encode for multiple HP1 isoforms and the molecular mechanisms that underpin their diverse functions in genome regulation remain poorly understood. In fission yeast, the two HP1 proteins Chp2 and Swi6 assume distinct roles and Chp2 is tightly associated with the nucleosome remodeling and deacetylation complex SHREC. Here we show that Chp2 directly engages the SHREC nucleosome remodeler subunit Mit1. The crystal structure of the interaction interface reveals an extraordinarily extensive and specific interaction between the chromoshadow domain of Chp2 and the N terminus of Mit1. The integrity of this interface is critical for high affinity binding and for heterochromatin formation. Comparison with Swi6 shows that the Chp2-Mit1 interface is highly selective and thereby provides the molecular basis for the functional specialization of an HP1 isoform.
We thank Yvan Pfister for technical help and Michael Hothorn and Ulrich Hohmann for help with ITC. We are grateful to Roman Ulm and Roman Podolec for help with yeast-two-hybrid. We thank Janet Partridge, Jun-ichi Nakayama, Robin Allshire, and Shiv Grewal for providing strains. We thank Chris Lima for supplying the Sumo expression vectors. We acknowledge the Swiss Light Source at the Paul Scherrer Institut, Villigen (SLS), Switzerland for provision of synchrotron radiation facilities and thank Vincent Olieric for assistance in using beam line PXIII. We thank the Functional Genomics Center Zurich for support with mass spectrometry analysis. We thank Michael Hothorn and Marc Bühler for helpful comments on the manuscript. This work was supported by the Swiss National Science Foundation SNF Professorship grants [PP00P3_139137, PP00P3_163760_1, PP00P3_172904 to T.S.]; Fondation Ernst et Lucie Schmidheiny, Fonds Constantin Topali and Société Académique de Genève (T.S.)
CitationGenes and Development, 2019, 33: 565-577
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology
- VoR (Version of Record)