In-solution structure and oligomerization of human histone deacetylase 6 - an integrative approach

FEBS J. 2023 Feb;290(3):821-836. doi: 10.1111/febs.16616. Epub 2022 Sep 19.


Human histone deacetylase 6 (HDAC6) is a structurally unique, multidomain protein implicated in a variety of physiological processes including cytoskeletal remodelling and the maintenance of cellular homeostasis. Our current understanding of the HDAC6 structure is limited to isolated domains, and a holistic picture of the full-length protein structure, including possible domain interactions, is missing. Here, we used an integrative structural biology approach to build a solution model of HDAC6 by combining experimental data from several orthogonal biophysical techniques complemented by molecular modelling. We show that HDAC6 is best described as a mosaic of folded and intrinsically disordered domains that in-solution adopts an ensemble of conformations without any stable interactions between structured domains. Furthermore, HDAC6 forms dimers/higher oligomers in a concentration-dependent manner, and its oligomerization is mediated via the positively charged N-terminal microtubule-binding domain. Our findings provide the first insights into the structure of full-length human HDAC6 and can be used as a basis for further research into structure function and physiological studies of this unique deacetylase.

Keywords: acetylation; analytical ultracentrifugation; intrinsically disordered regions; oligomerization; small-angle X-ray scattering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Histone Deacetylase 6 / chemistry
  • Histone Deacetylase 6 / genetics
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases* / metabolism
  • Humans
  • Microtubules* / metabolism


  • Histone Deacetylase 6
  • Histone Deacetylases
  • Histone Deacetylase Inhibitors

Associated data

  • RefSeq/NP_006035.2