title: Two catalytic domains are required for protein deacetylation.
abstract: Histone deacetylase (HDAC)-6 was recently identified as a dual substrate, possibly multisubstrate, deacetylase that can act both on acetylated histone tails and on alpha-tubulin acetylated on Lys40. HDAC-6 is unique among deacetylases in having two hdac domains, and we have used this enzyme as a useful model to dissect the structural requirements for the deacetylation reaction. In this report, we show that both hdac domains are required for the intact deacetylase activity of HDAC-6 in vitro and in vivo. The spatial arrangement of these two domains in HDAC-6 is essential and alteration of the linker region between the two domains severely affects the catalytic activity. Artificial chimeric HDACs, made by replacing the hdac domains in HDAC-6 with corresponding domains from other class II HDACs, show de novo deacetylase activity. Taken together, our results demonstrate for the first time that the spatial arrangement of hdac domains is critical for in vivo deacetylation reaction and may provide a useful model for the development of novel HDAC inhibitors.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, P. O. Box 2543, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Benoit
authors.initials: B
authors.lastname: Gilquin
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
mesh_terms: D016475:3T3 Cells; D000107:Acetylation; D000818:Animals; D020134:Catalytic Domain; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; D014404:Tubulin; C498618:Hdac5 protein, mouse; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases