Crystal Structure of a Bacterial Class 2 Histone Deacetylase Homologue

Nielsen, T.K.; Hildmann, Christian; Dickmanns, Achim; Schwienhorst, Andreas; Ficner, Ralf

doi:10.1016/j.jmb.2005.09.065

Cited by 148 publications

(165 citation statements)

References 56 publications

(72 reference statements)

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“…7). In the structures of the bacterial HDAC homolog HDLP (7), HDAC8 (9, 10), and a class II bacterial homolog (8), this Y is located close to the end of a ␤-strand, a structural element conserved among all these homologs including the local backbone conformation (data not shown). To act as transition-state stabilizer, the Y side chain has to be oriented along the ␤-strand, as seen in all these crystal structures.…”

Section: Sequence and Structure Analysis Indicates That Vertebrate CLmentioning

confidence: 99%

“…All three classes are distinct from the sirtuin-family enzymes (class III) (6) in the catalytic domain primary sequence and three-dimensional structure, and in the catalytic mechanism. Several HDAC structures confirm the presence of a common catalytic site where a Zn ion coordinated by highly conserved residues contacts the hydroxamate moiety of HDAC inhibitors (HDACis) (7)(8)(9)(10). On this basis, a common enzymatic mechanism has been proposed focused on the Zn-catalyzed hydrolysis of the acetyl-lysine amide bond (7).…”

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confidence: 99%

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Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases

Lahm¹,

Paolini²,

Pallaoro³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

488

530

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Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on standard substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-N2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this ''gain of function phenotype'' could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro. Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.catalytic domain ͉ enzymatic activity ͉ trifluoroacetyl-lysine ͉ gain of function

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Section: Sequence and Structure Analysis Indicates That Vertebrate CLmentioning

confidence: 99%

mentioning

confidence: 99%

Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases

Lahm¹,

Paolini²,

Pallaoro³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

488

530

View full text Add to dashboard Cite

show abstract

“…This region, which shows the highest homology to yeast Hda1 (52, 53, 51 and 51% similarity for HDAC4, -5, -7 and -9, respectively) is highly conserved among class IIa members (around 80% sequence similarity). Structural analysis of FB188 HDAH, a bacterial HDAC-like protein with significant homology to the catalytic domain of class II HDACs, has revealed that while the canonical fold of their catalytic pocket is very similar, there are several important differences between class I and class II HDACs that mainly concern the entrance region of the active site cavity and the outer charge transfer relay system (Finnin et al, 1999;Somoza et al, 2004;Vannini et al, 2004;Nielsen et al, 2005). This might explain why, in contrast to class I HDACs, researchers in the field have remained remarkably unsuccessful at obtaining enzymatically active class IIa HDACs in recombinant forms in vitro (Hassig et al, 1998;Hu et al, 2000).…”

Section: Structure Of Class Iia Hdacs: the C-terminal Deacetylase Domainmentioning

confidence: 99%

Class IIa histone deacetylases: regulating the regulators

2007

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“…More recently, there was a report of a bacterial class II HDAC homologue FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) bound to the reaction product acetate and hydroxamic acid inhibitors (Nielsen et al, 2005). Sequence alignment of FB188 HDAH with other class I and II HDACs shows 30-35% sequence identity with the two HDAC domains of the class II human HDAC, HDAC6, and only about 20% identity with the class I HDACs, HDLP and HDAC8.…”

Section: Structural Insights Into Catalysis and Inhibitor Binding By mentioning

confidence: 99%

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

2007

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The post-translational modification of histones plays an important role in chromatin regulation, a process that insures the fidelity of gene expression and other DNA transactions. Of the enzymes that mediate post-translation modification, the histone acetyltransferase (HAT) and histone deacetylase (HDAC) proteins that add and remove acetyl groups to and from target lysine residues within histones, respectively, have been the most extensively studied at both the functional and structural levels. Not surprisingly, the aberrant activity of several of these enzymes have been implicated in human diseases such as cancer and metabolic disorders, thus making them important drug targets. Significant mechanistic insights into the function of HATs and HDACs have come from the X-ray crystal structures of these enzymes both alone and in liganded complexes, along with associated enzymatic and biochemical studies. In this review, we will discuss what we have learned from the structures and related biochemistry of HATs and HDACs and the implications of these findings for the design of protein effectors to regulate gene expression and treat disease.

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Crystal Structure of a Bacterial Class 2 Histone Deacetylase Homologue

Cited by 148 publications

References 56 publications

Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases

Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases

Class IIa histone deacetylases: regulating the regulators

Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design

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