Concerted regulation of ISWI by an autoinhibitory domain and the H4 N-terminal tail

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Abstract

ISWI-family nucleosome remodeling enzymes need the histone H4 N-terminal tail to mobilize nucleosomes. Here we mapped the H4-tail binding pocket of ISWI. Surprisingly the binding site was adjacent to but not overlapping with the docking site of an auto-regulatory motif, AutoN, in the N-terminal region (NTR) of ISWI, indicating that AutoN does not act as a simple pseudosubstrate as suggested previously. Rather, AutoN cooperated with a hitherto uncharacterized motif, termed AcidicN, to confer H4-tail sensitivity and discriminate between DNA and nucleosomes. A third motif in the NTR, ppHSA, was functionally required in vivo and provided structural stability by clamping the NTR to Lobe 2 of the ATPase domain. This configuration is reminiscent of Chd1 even though Chd1 contains an unrelated NTR. Our results shed light on the intricate structural and functional regulation of ISWI by the NTR and uncover surprising parallels with Chd1.

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Johanna Ludwigsen

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Sabrina Pfennig

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Ashish K Singh

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Christina Schindler

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Nadine Harrer

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

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The authors declare that no competing interests exist.
Ignasi Forné

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

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The authors declare that no competing interests exist.
Martin Zacharias

Physics Department, Technische Universität München, Garching, Germany

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The authors declare that no competing interests exist.
Felix Mueller-Planitz

Biomedical Center, Ludwig-Maximilians-Universität München, Martinsried, Germany

For correspondence
felix.mueller-planitz@med.uni-muenchen.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8273-6473

Funding

Ernst Schering Foundation

Johanna Ludwigsen

Deutscher Akademischer Austauschdienst

Ashish K Singh

Deutsche Forschungsgemeinschaft (CIPSM)

Martin Zacharias

Deutsche Forschungsgemeinschaft (MU 3613/1-1 MU 3613/3-1 SFB 1064/1TP-A07)

Felix Mueller-Planitz

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.