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Review
. 2005 Apr;25(8):2873-84.
doi: 10.1128/MCB.25.8.2873-2884.2005.

Class II histone deacetylases: from sequence to function, regulation, and clinical implication

Xiang-Jiao Yang  1 , Serge Grégoire
Affiliations
Review

Class II histone deacetylases: from sequence to function, regulation, and clinical implication

Xiang-Jiao Yang et al. Mol Cell Biol. 2005 Apr.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Domain organization of Hda1 and related proteins from fission yeast (A), worms (B), flies (C), humans (D), and plants (E). For each protein, only one isoform (usually the full-length isoform) is drawn, with its total number of residues and database accession number shown at the right. The deacetylase domain of Hda1 is depicted with a rectangle containing a yellow center flanked by orange areas. Similar rectangles are used to illustrate the deacetylase domains in Hda1-like proteins, with respective sequence identity/similarity to that of Hda1 listed. The C-terminal domains (shaded rectangles) of Hda1 and Clr3 are homologous. Dark bars, similar N-terminal domains and C-terminal tails of class IIa metazoan HDACs; small green boxes, MEF2-binding motifs; boxes labeled S (for serine), 14-3-3 binding motifs; boxes labeled D (for Asp289) and K (for Lys559), caspase cleavage and sumoylation sites on HDAC4, respectively. NES, nuclear export signal; SE14, SerGlu-containing tetradecapeptide repeats; ZF, zinc finger.
FIG. 2.
FIG. 2.
(A and B) Sequence alignment of the MEF2-binding motif (A) and the NLS (B) of class IIa HDACs. Residues invariant and highly conserved among at least four sequences are shaded. Arrows, residues known to be essential for the NLS function, 14-3-3 association, or MEF2 binding; solid line, region critical for Ca2+/calmodulin binding; asterisk, potential Dyrk1B phosphorylation site. (C) Sequence similarity between the HUB finger of HDAC6 and motifs in other proteins. Identical and highly conserved residues are shaded. Only the central region of the HUB finger is similar to USP49 and BRAP2. Residues invariant and highly conserved among at least 75% of the sequences are shaded.
FIG. 3.
FIG. 3.
Cartoon depicting mechanisms involved in the regulation of HDAC4. It is actively imported and exported; the relative trafficking rate dictates its subcellular distribution. Cell signaling activates CaMK, PKD, and perhaps other kinases, thereby leading to site-specific phosphorylation of HDAC4 and association with 14-3-3 proteins. 14-3-3 binding then shifts the trafficking equilibrium of HDAC4 toward cytoplasmic accumulation. Unknown phosphatases dephosphorylate HDAC4 and dissociate it from 14-3-3 proteins for translocation to the nucleus, where it binds to sequence-specific transcription factors (TF) to repress transcription. The binding can be direct or mediated by a corepressor. Caspase 3 cleaves HDAC4 to generate the N-terminal (N) and C-terminal (C) fragments (Fig. 1D), with the former translocating to the nucleus as a transcriptional corepressor. HDAC4 may also be subject to proteosomal degradation. Dyrk1B and related kinases may phosphorylate HDAC4 and inhibit its nuclear import. Except for a few details, this model can be extended to other class IIa HDACs.
FIG. 4.
FIG. 4.
Sequence comparison of different α-tubulins. The peptides are flanked with the starting and ending positions, and residues invariant among at least five sequences are shaded. The sequence accession numbers are shown in parentheses at the right. Arrow, acetylation site. The acetylatable lysine residue is replaced by leucine in the only two α-tubulins found in budding yeast.
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