Schweipert, Markus ; Nehls, Thomas ; Frühauf, Anton ; Debarnot, Cecilé ; Kumar, Adarsh ; Knapp, Stefan ; Lermyte, Frederik ; Meyer‐Almes, Franz‐Josef (2024)
The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation.
In: Protein Science, 33 (3)
doi: 10.1002/pro.4917
Artikel, Bibliographie
Dies ist die neueste Version dieses Eintrags.
Kurzbeschreibung (Abstract)
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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Schweipert, Markus ; Nehls, Thomas ; Frühauf, Anton ; Debarnot, Cecilé ; Kumar, Adarsh ; Knapp, Stefan ; Lermyte, Frederik ; Meyer‐Almes, Franz‐Josef |
| Art des Eintrags: | Bibliographie |
| Titel: | The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation |
| Sprache: | Englisch |
| Publikationsjahr: | März 2024 |
| Ort: | Hoboken |
| Verlag: | Wiley |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Protein Science |
| Jahrgang/Volume einer Zeitschrift: | 33 |
| (Heft-)Nummer: | 3 |
| Kollation: | 15 Seiten |
| DOI: | 10.1002/pro.4917 |
| Zugehörige Links: | |
| Kurzbeschreibung (Abstract): | 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. |
| Freie Schlagworte: | allosteric regulation, conformation sensitive mass spectrometry, conformational, conformational equilibrium, conformations, HDAC4, ligand binding, NMR, transient binding pockets |
| ID-Nummer: | Artikel-ID: e4917 |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut |
| Hinterlegungsdatum: | 13 Jun 2024 06:23 |
| Letzte Änderung: | 17 Jun 2024 09:22 |
| PPN: | 519186125 |
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| Suche nach Titel in: | TUfind oder in Google |
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The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation. (deposited 12 Jun 2024 11:51)
- The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation. (deposited 13 Jun 2024 06:23) [Gegenwärtig angezeigt]
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