Cited by 407Epigenetics and DNA MethylationGenomics and Chromatin DynamicsCancer-related gene regulation

Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases

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Horton, John R, Upadhyay, Anup K, Qi, Hank H, Zhang, Xing, Shi, Yang, Cheng, Xiaodong·2010·Nature Structural & Molecular Biology

Abstract

Combinatorial readout of multiple covalent histone modifications is poorly understood. We provide insights into how an activating histone mark, in combination with linked repressive marks, is differentially 'read' by two related human demethylases, PHF8 and KIAA1718 (also known as JHDM1D). Both enzymes harbor a plant homeodomain (PHD) that binds Lys4-trimethylated histone 3 (H3K4me3) and a jumonji domain that demethylates either H3K9me2 or H3K27me2. The presence of H3K4me3 on the same peptide as H3K9me2 makes the doubly methylated peptide a markedly better substrate of PHF8, whereas the presence of H3K4me3 has the opposite effect, diminishing the H3K9me2 demethylase activity of KIAA1718 without adversely affecting its H3K27me2 activity. The difference in substrate specificity between the two is explained by PHF8 adopting a bent conformation, allowing each of its domains to engage its respective target, whereas KIAA1718 adopts an extended conformation, which prevents its access to H3K9me2 by its jumonji domain when its PHD engages H3K4me3.

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Authors
Horton, J. R., Upadhyay, A. K., Qi, H. H., Zhang, X., Shi, Y., & Cheng, X.
Affiliations
  • Emory University (US)
  • Boston Children's Hospital (US)
Corresponding author
Cheng, Xiaodong
Venue
Nature Structural & Molecular Biology
Published
2009-12-20
Volume
17
Issue
1
Pages
38-43
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W2132614547
Cited by
389
References
46
Citations by year
2026: 10 · 2025: 14 · 2024: 22 · 2023: 12 · 2022: 13 · 2021: 24 · 2020: 22 · 2019: 27 · 2018: 18 · 2017: 19 · 2016: 30 · 2015: 27 · 2014: 27 · 2013: 28 · 2012: 26
FWCI
12.25
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Public Health Service (NCI118487)
  • National Institute of General Medical Sciences (GM058012, R01GM058012, R01GM068680, GM06860)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R56DK082678, DK082678)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords
PHF8, plant homeodomain, histone lysine demethylation, H3K4me3, H3K9me2, H3K27me2, substrate specificity, protein conformation, histone modifications, transcriptional activation, histone reader proteins
MeSH terms
Histones, Humans, Models, Molecular, Oxidoreductases, N-Demethylating, Protein Binding, Protein Conformation, Substrate Specificity, Transcription Factors, Protein Structure, Tertiary, F-Box Proteins, Histone Demethylases, Jumonji Domain-Containing Histone Demethylases

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