Letter | Published:

Structure and regulation of the chromatin remodeller ISWI

Nature volume 540, pages 466469 (15 December 2016) | Download Citation

Abstract

ISWI is a member of the SWI2/SNF2 family of chromatin remodellers1,2, which also includes Snf2, Chd1, and Ino80. ISWI is the catalytic subunit of several chromatin remodelling complexes, which mobilize nucleosomes along genomic DNA, promoting replication progression, transcription repression, heterochromatin formation, and many other nuclear processes3,4,5. The ATPase motor of ISWI is an autonomous remodelling machine6, whereas its carboxy (C)-terminal HAND–SAND–SLIDE (HSS) domain functions in binding extranucleosomal linker DNA7,8,9,10. The activity of the catalytic core of ISWI is inhibited by the regulatory AutoN and NegC domains, which are in turn antagonized by the H4 tail and extranucleosomal DNA, respectively, to ensure the appropriate chromatin landscape in cells11. How AutoN and NegC inhibit ISWI and regulate its nucleosome-centring activity remains elusive. Here we report the crystal structures of ISWI from the thermophilic yeast Myceliophthora thermophila and its complex with a histone H4 peptide. Our data show the amino (N)-terminal AutoN domain contains two inhibitory elements, which collectively bind the second RecA-like domain (core2), holding the enzyme in an inactive conformation. The H4 peptide binds to the core2 domain coincident with one of the AutoN-binding sites, explaining the ISWI activation by H4. The H4-binding surface is conserved in Snf2 and functions beyond AutoN regulation. The C-terminal NegC domain is involved in binding to the core2 domain and functions as an allosteric element for ISWI to respond to the extranucleosomal DNA length.

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Acknowledgements

We thank S. Fan at the centre of structure biology (Tsinghua University) and the staff at beamline BL17U of Shanghai Synchrotron Radiation Facility for help with diffraction data collection, and the Tsinghua University Branch of the China National Center for Protein Sciences Beijing for providing facility support. This work was supported by the Chinese Key Research Plan-Protein Sciences (2014CB910100), the National Natural Science Foundation of China (31570731, 31270762), and the ‘Junior One Thousand Talents’ program to Z.C.

Author information

Author notes

    • Lijuan Yan
    •  & Li Wang

    These authors contributed equally to this work.

Affiliations

  1. MOE Key Laboratory of Protein Science, Tsinghua University, Beijing, 100084, China

    • Lijuan Yan
    • , Li Wang
    • , Yuanyuan Tian
    • , Xian Xia
    •  & Zhucheng Chen
  2. School of Life Science, Tsinghua University, Beijing, 100084, China

    • Lijuan Yan
    • , Li Wang
    • , Yuanyuan Tian
    • , Xian Xia
    •  & Zhucheng Chen

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Contributions

L.Y. and L.W. prepared the proteins and performed the biochemical analyses with the help from X.X. and Y.T.; L.Y. crystallized the proteins; Z.C. wrote the manuscript with help from all authors; Z.C. directed and supervised all the research.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Zhucheng Chen.

Reviewer Information

Nature thanks B. Bartholomew and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20590

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