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Active Site Metal Identity Alters Histone Deacetylase 8 Substrate Selectivity: A Potential Novel Regulatory Mechanism

  1. Author:
    Castaneda, Carol Ann
    Lopez, Jeff
    Joseph, Caleb G.
    Scholle, Michael D.
    Mrksich, Milan
    Fierke, Carol A.

  2. Author Address

    Univ Michigan, Program Chem Biol, Ann Arbor, MI 48109 USA.Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA.Northwestern Univ, Dept Chem, Evanston, IL 60208 USA.Northwestern Univ, Dept Biomed Engn, Evanston, IL 60208 USA.Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA.Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA.SAMDI Tech Inc, 3440 S Dearborn St,Suite 220S, Chicago, IL 60616 USA.Abbott Dept, 04ZU,Bldg AP8B,100 Abbott Pk Rd, Abbott Pk, IL 60064 USA.NCI, Chem Biol Lab, 376 Boyles St,Bldg 376, Frederick, MD 21702 USA.
    1. Year: 2017
    2. Date: OCT 24
  2. Journal: BIOCHEMISTRY
  3. AMER CHEMICAL SOC,
    1. 56
    2. 42
    3. Pages: 5663-5670
  5. Type of Article: Article
  6. ISSN: 0006-2960
  1. Abstract:

    Histone deacetylase 8 (HDAC8) is a well-characterized member of the class I acetyl-lysine deacetylase (HDAC) family. Previous work has shown that the efficiency of HDAC8-catalyzed deacetylation of a methylcoumarin peptide varies depending on the identity of the divalent metal ion in the HDAC8 active site. Here we demonstrate that both HDAC8 activity and substrate selectivity for a diverse range of peptide substrates depend on the identity of the active site metal ion. Varied deacetylase activities of Fe(II)- and Zn(II)-HDAC8 toward an array of peptide substrates were identified using self-assembled monolayers for matrix-assisted laser desorption ionization (SAMDI) mass spectrometry. Subsequently, the metal dependence of deacetylation of peptides of biological interest was measured using an in vitro peptide assay. While Fe(II)-HDAC8 is generally more active than Zn(II)-HDAC8, the Fe(II)/Zn(II) HDAC8 activity ratio varies widely (from 2 to 150) among the peptides tested. These data provide support for the hypothesis that HDAC8 may undergo metal switching in vivo that, in turn, may regulate its activity. However, future studies are needed to explore the identity of the metal ion bound to HDAC8 in cells under varied conditions.

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External Sources

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  2. DOI: 10.1021/acs.biochem.7b00851
  3. PMID: 28937750
  4. View record in Web of Science®
  5. WOS: 000413885000007

Library Notes

  1. Fiscal Year: FY2017-2018
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