PUBLICATION
Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates
- Authors
- Varga, J.K., Diffley, K., Welker Leng, K.R., Fierke, C.A., Schueler-Furman, O.
- ID
- ZDB-PUB-220309-1
- Date
- 2022
- Source
- Scientific Reports 12: 1788 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Zebrafish/metabolism*
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism
- Enzyme Assays
- Substrate Specificity
- Humans
- Histone Deacetylase 6/chemistry*
- Histone Deacetylase 6/metabolism*
- Protein Conformation
- PubMed
- 35110592 Full text @ Sci. Rep.
Citation
Varga, J.K., Diffley, K., Welker Leng, K.R., Fierke, C.A., Schueler-Furman, O. (2022) Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates. Scientific Reports. 12:1788.
Abstract
Histone deacetylases play important biological roles well beyond the deacetylation of histone tails. In particular, HDAC6 is involved in multiple cellular processes such as apoptosis, cytoskeleton reorganization, and protein folding, affecting substrates such as ɑ-tubulin, Hsp90 and cortactin proteins. We have applied a biochemical enzymatic assay to measure the activity of HDAC6 on a set of candidate unlabeled peptides. These served for the calibration of a structure-based substrate prediction protocol, Rosetta FlexPepBind, previously used for the successful substrate prediction of HDAC8 and other enzymes. A proteome-wide screen of reported acetylation sites using our calibrated protocol together with the enzymatic assay provide new peptide substrates and avenues to novel potential functional regulatory roles of this promiscuous, multi-faceted enzyme. In particular, we propose novel regulatory roles of HDAC6 in tumorigenesis and cancer cell survival via the regulation of EGFR/Akt pathway activation. The calibration process and comparison of the results between HDAC6 and HDAC8 highlight structural differences that explain the established promiscuity of HDAC6.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping