HDAC8 substrate selectivity is determined by long- and short-range interactions leading to enhanced reactivity for full-length histone substrates compared with peptides

Castañeda, Carol Ann; Wolfson, Noah A.; Leng, Katherine R. Welker; Kuo, Yin-Ming; Andrews, Andrew J.; Fierke, Carol A.

doi:10.1074/jbc.m117.811026

Cited by 36 publications

(46 citation statements)

References 65 publications

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“…However, although the more prominent contribution of proximal residues is evident, substrate recognition by HDAC6 is likely to be regulated by a combination of both proximal and distal residues acting synergically/antagonistically. Similar observations regarding the combination of short-and long-range interactions for substrate recognition were recently reported for HDAC8 and histone substrates (37,38).…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2018

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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. FASEB J. 33,4035–4045 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 87%

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

et al. 2018

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“…Therefore, this motif is likely to be conducive to the development of HDAC8-specific inhibitors (Ingham et al, 2016). Furthermore, its crystal structure indicates that dimerization occurs at the binding interface between HDAC8 and its substrate (Castaneda et al, 2017).…”

Section: Class I Hdacsmentioning

confidence: 99%

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Guo

Tian

Zhu

2020

Front. Cell Dev. Biol.

199

135

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Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (N ε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

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“…However, it is not known whether these peptides are a reliable model for actual protein substrates. Recent research suggests that long range interactions, which are obviously not present with peptide substrates, at least sometimes do play a significant role in KDAC reactivity 95 . Note that we are excluding from consideration studies that utilize acetylated lysine in an unnatural context, such as conjugated to a fluorophore, as such substrates have not proven useful for understanding biologically relevant substrates 88,96 .…”

Section: Approaches For Kdac Substrate Identificationmentioning

confidence: 99%

Critical review of non‐histone human substrates of metal‐dependent lysine deacetylases

Toro

Watt

2020

FASEB j.

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Lysine acetylation is a posttranslational modification that occurs on thousands of human proteins, most of which are cytoplasmic. Acetylated proteins are involved in numerous cellular processes and human diseases. Therefore, how the acetylation/deacetylation cycle is regulated is an important question. Eleven metal‐dependent lysine deacetylases (KDACs) have been identified in human cells. These enzymes, along with the sirtuins, are collectively responsible for reversing lysine acetylation. Despite several large‐scale studies which have characterized the acetylome, relatively few of the specific acetylated residues have been matched to a proposed KDAC for deacetylation. To understand the function of lysine acetylation, and its association with diseases, specific KDAC‐substrate pairs must be identified. Identifying specific substrates of a KDAC is complicated both by the complexity of assaying relevant activity and by the non‐catalytic interactions of KDACs with cellular proteins. Here, we discuss in vitro and cell‐based experimental strategies used to identify KDAC‐substrate pairs and evaluate each for the purpose of directly identifying non‐histone substrates of metal‐dependent KDACs. We propose criteria for a combination of reproducible experimental approaches that are necessary to establish a direct enzymatic relationship. This critical analysis of the literature identifies 108 proposed non‐histone substrate‐KDAC pairs for which direct experimental evidence has been reported. Of these, five pairs can be considered well‐established, while another thirteen pairs have both cell‐based and in vitro evidence but lack independent replication and/or sufficient cell‐based evidence. We present a path forward for evaluating the remaining substrate leads and reliably identifying novel KDAC substrates.

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HDAC8 substrate selectivity is determined by long- and short-range interactions leading to enhanced reactivity for full-length histone substrates compared with peptides

Cited by 36 publications

References 65 publications

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

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

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Critical review of non‐histone human substrates of metal‐dependent lysine deacetylases

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