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A distal regulatory region of a class I human histone deacetylase

Author

Listed:
  • Nicolas D. Werbeck

    (University College London
    Nuvisan ICB GmbH, Innovation Campus Berlin)

  • Vaibhav Kumar Shukla

    (University College London)

  • Micha B. A. Kunze

    (University College London)

  • Havva Yalinca

    (University College London)

  • Ruth B. Pritchard

    (University College London)

  • Lucas Siemons

    (University College London)

  • Somnath Mondal

    (University College London)

  • Simon O. R. Greenwood

    (University College London
    University College London)

  • John Kirkpatrick

    (University College London)

  • Charles M. Marson

    (University College London)

  • D. Flemming Hansen

    (University College London)

Abstract

Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.

Suggested Citation

  • Nicolas D. Werbeck & Vaibhav Kumar Shukla & Micha B. A. Kunze & Havva Yalinca & Ruth B. Pritchard & Lucas Siemons & Somnath Mondal & Simon O. R. Greenwood & John Kirkpatrick & Charles M. Marson & D. F, 2020. "A distal regulatory region of a class I human histone deacetylase," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17610-w
    DOI: 10.1038/s41467-020-17610-w
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    Cited by:

    1. Mandy S. M. Wan & Reyhan Muhammad & Marios G. Koliopoulos & Theodoros I. Roumeliotis & Jyoti S. Choudhary & Claudio Alfieri, 2023. "Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Gogulan Karunanithy & Vaibhav Kumar Shukla & D. Flemming Hansen, 2024. "Solution-state methyl NMR spectroscopy of large non-deuterated proteins enabled by deep neural networks," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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