Inositol phosphates and core subunits of the Sin3L/Rpd3L histone deacetylase (HDAC) complex up-regulate deacetylase activity.
Amino Acid Sequence
DNA-Binding Proteins
/ metabolism
HEK293 Cells
Histone Deacetylase 1
/ metabolism
Histone Deacetylases
/ metabolism
Humans
Inositol Phosphates
/ chemistry
Models, Theoretical
Nuclear Receptor Co-Repressor 1
Protein Binding
Repressor Proteins
/ metabolism
Retinoblastoma-Binding Protein 4
/ metabolism
Transcription Factors
Transcriptional Activation
Zinc Fingers
allosteric regulation
chromatin modification
cofactor-mediated protein–protein interaction
convergent evolution
epigenetics
gene expression
histone deacetylase (HDAC)
inositol phosphate
protein–protein interaction
signaling
transcription regulation
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
20 09 2019
20 09 2019
Historique:
received:
12
06
2019
revised:
25
07
2019
pubmed:
31
7
2019
medline:
13
5
2020
entrez:
31
7
2019
Statut:
ppublish
Résumé
The constitutively nuclear histone deacetylases (HDACs) 1, 2, and 3 erase acetyl marks on acetyllysine residues, alter the landscape of histone modifications, and modulate chromatin structure and dynamics and thereby crucially regulate gene transcription in higher eukaryotes. Nuclear HDACs exist as at least six giant multiprotein complexes whose nonenzymatic subunits confer genome targeting specificity for these enzymes. The deacetylase activity of HDACs has been shown previously to be enhanced by inositol phosphates, which also bridge the catalytic domain in protein-protein interactions with SANT (Swi3, Ada2, N-Cor, and TFIIIB) domains in all HDAC complexes except those that contain the Sin3 transcriptional corepressors. Here, using purified recombinant proteins, coimmunoprecipitation and HDAC assays, and pulldown and NMR experiments, we show that HDAC1/2 deacetylase activity in one of the most ancient and evolutionarily conserved Sin3L/Rpd3L complexes is inducibly up-regulated by inositol phosphates but involves interactions with a zinc finger motif in the Sin3-associated protein 30 (SAP30) subunit that is structurally unrelated to SANT domains, indicating convergent evolution at the functional level. This implies that this mode of regulation has evolved independently multiple times and provides an evolutionary advantage. We also found that constitutive association with another core subunit, Rb-binding protein 4 chromatin-binding factor (RBBP4), further enhances deacetylase activity, implying both inducible and constitutive regulatory mechanisms within the same HDAC complex. Our results indicate that inositol phosphates stimulate HDAC activity and that the SAP30 zinc finger motif performs roles similar to that of the unrelated SANT domain in promoting the SAP30-HDAC1 interaction and enhancing HDAC activity.
Identifiants
pubmed: 31358618
pii: S0021-9258(20)32079-2
doi: 10.1074/jbc.RA119.009780
pmc: PMC6755813
doi:
Substances chimiques
DNA-Binding Proteins
0
Inositol Phosphates
0
NCOR1 protein, human
0
Nuclear Receptor Co-Repressor 1
0
RBBP4 protein, human
0
Repressor Proteins
0
Retinoblastoma-Binding Protein 4
0
SAP30 protein, human
0
SMARCC1 protein, human
0
Transcription Factors
0
HDAC1 protein, human
EC 3.5.1.98
Histone Deacetylase 1
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Banques de données
PDB
['5ICN', '4A69', '2KDP']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13928-13938Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008382
Pays : United States
Informations de copyright
© 2019 Marcum and Radhakrishnan.
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