Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism

Idelisse Ortiz Torres; Kristopher M Kuchenbecker; Chimno I Nnadi; Robert J Fletterick; Mark J S Kelly; Danica Galonić Fujimori

doi:10.1038/ncomms7204

Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism

Nat Commun. 2015 Feb 17:6:6204. doi: 10.1038/ncomms7204.

Authors

Idelisse Ortiz Torres¹, Kristopher M Kuchenbecker², Chimno I Nnadi³, Robert J Fletterick⁴, Mark J S Kelly⁵, Danica Galonić Fujimori⁶

Affiliations

¹ 1] Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Chemistry and Chemical Biology Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
² 1] Department of Biochemistry and Biophysics, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Biophysics Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
³ 1] Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Chemistry and Chemical Biology Graduate Program, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [3] UCSF Medical Scientist Training Program, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA.
⁴ Department of Biochemistry and Biophysics, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
⁵ Department of Pharmaceutical Chemistry, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.
⁶ 1] Department of Cellular and Molecular Pharmacology, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA [2] Department of Pharmaceutical Chemistry, University of California, 600 16th Street, Genentech Hall, San Francisco, California 94158, USA.

Abstract

The retinoblastoma binding protein KDM5A removes methyl marks from lysine 4 of histone H3 (H3K4). Misregulation of KDM5A contributes to the pathogenesis of lung and gastric cancers. In addition to its catalytic jumonji C domain, KDM5A contains three PHD reader domains, commonly recognized as chromatin recruitment modules. It is unknown whether any of these domains in KDM5A have functions beyond recruitment and whether they regulate the catalytic activity of the demethylase. Here using biochemical and nuclear magnetic resonance (NMR)-based structural studies, we show that the PHD1 preferentially recognizes unmethylated H3K4 histone tail, product of KDM5A-mediated demethylation of tri-methylated H3K4 (H3K4me3). Binding of unmodified H3 peptide to the PHD1 stimulates catalytic domain-mediated removal of methyl marks from H3K4me3 peptide and nucleosome substrates. This positive-feedback mechanism--enabled by the functional coupling between a reader and a catalytic domain in KDM5A--suggests a model for the spread of demethylation on chromatin.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Algorithms
Amino Acid Sequence
Animals
Catalytic Domain
Cell Line
Chromatin / chemistry
Circular Dichroism
Gene Expression Regulation, Neoplastic*
Glutathione Transferase / metabolism
Humans
Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
Insecta
Kinetics
Lysine / chemistry
Magnetic Resonance Spectroscopy
Molecular Sequence Data
Nucleosomes / chemistry
Peptides / chemistry
Protein Binding
Protein Conformation
Recombinant Proteins / chemistry
Retinoblastoma-Binding Protein 2 / metabolism*
Sequence Homology, Amino Acid

Substances

Chromatin
Nucleosomes
Peptides
Recombinant Proteins
KDM5A protein, human
Retinoblastoma-Binding Protein 2
EGLN2 protein, human
Hypoxia-Inducible Factor-Proline Dioxygenases
Glutathione Transferase
Lysine

Grants and funding

T32 GM008284/GM/NIGMS NIH HHS/United States