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The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation

  • Human histone deacetylase 4 (HDAC4) is a key epigenetic regulator involved in a number of important cellular processes. This makes HDAC4 a promising target for the treatment of several cancers and neurodegenerative diseases, in particular Huntington's disease. HDAC4 is highly regulated by phosphorylation and oxidation, which determine its nuclear or cytosolic localization, and exerts its function through multiple interactions with other proteins, forming multiprotein complexes of varying composition. The catalytic domain of HDAC4 is known to interact with the SMRT/NCOR corepressor complex when the structural zinc-binding domain (sZBD) is intact and forms a closed conformation. Crystal structures of the HDAC4 catalytic domain have been reported showing an open conformation of HDAC4 when bound to certain ligands. Here, we investigated the relevance of this HDAC4 conformation under physiological conditions in solution. We show that proper zinc chelation in the sZBD is essential for enzyme function. Loss of the structural zinc ion not only leads to a massive decrease in enzyme activity, but it also has serious consequences for the overall structural integrity and stability of the protein. However, the Zn2+ free HDAC4 structure in solution is incompatible with the open conformation. In solution, the open conformation of HDAC4 was also not observed in the presence of a variety of structurally divergent ligands. This suggests that the open conformation of HDAC4 cannot be induced in solution, and therefore cannot be exploited for the development of HDAC4-specific inhibitors.

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Metadaten
Author:Markus Schweipert, Thomas Nehls, Anton Frühauf, Cecilé Debarnot, Adarsh Kumar, Stefan Knapp, Frederik Lermyte, Franz‐Josef Meyer‐AlmesORCiD
URN:urn:nbn:de:hebis:ds114-opus4-4344
DOI:https://doi.org/10.1002/pro.4917
ISSN:0961-8368
ISSN:1469-896X
Parent Title (English):Protein Science
Publisher:John Wiley & Sons, Inc.
Place of publication:Hoboken, USA
Document Type:Article
Language:English
Year of Completion:2024
Publishing Institution:Hochschule Darmstadt
Release Date:2024/04/16
Tag:HDAC4; NMR; allosteric regulation; conformation sensitive mass spectrometry; conformational; conformational equilibrium; conformations; ligand binding; transient binding pockets
GND Keyword:-
Volume:33
Issue:3
Page Number:15
Note:
Originalveröffentlichung:  Schweipert M, Nehls T, Frühauf A, Debarnot C, Kumar A, Knapp S, et al. The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation. Protein Science. 2024; 33(3):e4917. https://doi.org/10.1002/pro.4917
Institutes:Chemie- und Biotechnologie
OpenAIRE:OpenAIRE
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International