The unraveling of substrate specificity of histone deacetylase 6 domains using acetylome peptide microarrays and peptide libraries

0505012 - BTÚ 2020 RIV US eng J - Journal Article
Kutil, Zsofia - Škultétyová, Ĺubica - Rauh, D. - Meleshin, M. - Šnajdr, Ivan - Nováková, Zora - Mikesova, Jana - Pavlíček, Jiří - Hadzima, Martin - Baranová, Petra - Havlínová, Barbora - Majer, Pavel - Schutkowski, M. - Bařinka, Cyril
The unraveling of substrate specificity of histone deacetylase 6 domains using acetylome peptide microarrays and peptide libraries.
FASEB Journal. Roč. 33, č. 3 (2019), s. 4035-4045. ISSN 0892-6638. E-ISSN 1530-6860
R&D Projects: GA ČR GA15-19640S; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036 ; RVO:61388963
Keywords : human acetylome * deacylation * deformylation
OECD category: Biochemistry and molecular biology; Biochemistry and molecular biology (UOCHB-X)
Impact factor: 4.966, year: 2019
Method of publishing: Open access
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201801680R

Histone deacetylase 6 (HDAC6) is a multidomain cytosolic hydrolase acting mostly on nonhistone protein substrates. Investigations of the substrate specificity of HDAC6 are confounded by the presence of 2 catalytically active deacetylase domains (DD1 and DD2). In this study, acetylome peptide microarrays and peptide libraries were used to map the substrate specificity of DD1 and DD2 of human HDAC6. The results show that DD1 is solely responsible for the deacetylation of substrates harboring the acetyllysine at their C terminus, whereas DD2 exclusively deacetylates peptides with an internal acetyllysine residue. Also, statistical analysis of the deacetylation data revealed amino acid preferences at individual positions flanking the acetyllysine, where glycine and arginine residues are favored at positions N-terminal to the central acetyllysine, negatively charged glutamate is strongly disfavored throughout the sequence. Finally, the deacylation activity of HDAC6 was profiled by using a panel of acyl derivatives of the optimized peptide substrate and showed that HDAC6 acts as a proficient deformylase. Our data thus offer a detailed insight into the substrate preferences of the individual HDAC6 domains at the peptide level, and these findings can in turn help in elucidating the biologic roles of the enzyme and facilitate the development of new domain-specific inhibitors as research tools or therapeutic agents.Kutil, Z., Skultetyova, L., Rauh, D., Meleshin, M., Snajdr, I., Novakova, Z., Mikesova, J., Pavlicek, J., Hadzima, M., Baranova, P., Havlinova, B., Majer, P., Schutkowski, M., Barinka, C. The unraveling of substrate specificity of histone deacetylase 6 domains using acetylome peptide microarrays and peptide libraries.
Permanent Link: http://hdl.handle.net/11104/0296540