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PDBsum entry 2naa
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Transcription
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PDB id
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2naa
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PDB id:
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| Name: |
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Transcription
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Title:
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Nsd1-phd_5-c5hch tandem domain structure
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Structure:
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Histone-lysine n-methyltransferase, h3 lysine-36 and h4 lysine-20 specific. Chain: a. Fragment: unp residues 2014-2104. Synonym: h3-k36-hmtase, h4-k20-hmtase, nuclear receptor-binding set domain-containing protein 1, nr-binding set domain-containing protein. Engineered: yes
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Gene: nsd1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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NMR struc:
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15 models
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Authors:
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A.Berardi,G.Quilici,D.Spiliotopoulos,G.Musco
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Key ref:
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A.Berardi
et al.
(2016).
Structural basis for PHDVC5HCHNSD1-C2HRNizp1 interaction: implications for Sotos syndrome.
Nucleic Acids Res,
44,
3448-3463.
PubMed id:
DOI:
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Date:
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22-Dec-15
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Release date:
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09-Mar-16
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PROCHECK
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Headers
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References
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O88491
(NSD1_MOUSE) -
Histone-lysine N-methyltransferase, H3 lysine-36 specific from Mus musculus
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Seq:
Struc:
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2588 a.a.
94 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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Enzyme class:
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E.C.2.1.1.357
- [histone H3]-lysine(36) N-dimethyltransferase.
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Reaction:
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L-lysyl36-[histone H3] + 2 S-adenosyl-L-methionine = N6,N6- dimethyl-L-lysyl36-[histone H3] + 2 S-adenosyl-L-homocysteine + 2 H+
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L-lysyl(36)-[histone H3]
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+
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2
×
S-adenosyl-L-methionine
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=
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N(6),N(6)- dimethyl-L-lysyl(36)-[histone H3]
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+
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2
×
S-adenosyl-L-homocysteine
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+
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2
×
H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nucleic Acids Res
44:3448-3463
(2016)
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PubMed id:
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Structural basis for PHDVC5HCHNSD1-C2HRNizp1 interaction: implications for Sotos syndrome.
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A.Berardi,
G.Quilici,
D.Spiliotopoulos,
M.A.Corral-Rodriguez,
F.Martin-Garcia,
M.Degano,
G.Tonon,
M.Ghitti,
G.Musco.
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ABSTRACT
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Sotos syndrome is an overgrowth syndrome caused by mutations within the
functional domains ofNSD1gene coding for NSD1, a multidomain protein regulating
chromatin structure and gene expression. In particular, PHDVC5HCHNSD1tandem
domain, composed by a classical (PHDV) and an atypical (C5HCH) plant
homeo-domain (PHD) finger, is target of several pathological missense-mutations.
PHDVC5HCHNSD1is also crucial for NSD1-dependent transcriptional regulation and
interacts with the C2HR domain of transcriptional repressor Nizp1 (C2HRNizp1)in
vitro To get molecular insights into the mechanisms dictating the
patho-physiological relevance of the PHD finger tandem domain, we solved its
solution structure and provided a structural rationale for the effects of seven
Sotos syndrome point-mutations. To investigate PHDVC5HCHNSD1role as structural
platform for multiple interactions, we characterized its binding to histone H3
peptides and to C2HRNizp1by ITC and NMR. We observed only very weak
electrostatic interactions with histone H3 N-terminal tails, conversely we
proved specific binding to C2HRNizp1 We solved C2HRNizp1solution structure and
generated a 3D model of the complex, corroborated by site-directed mutagenesis.
We suggest a mechanistic scenario where NSD1 interactions with cofactors such as
Nizp1 are impaired by PHDVC5HCHNSD1pathological mutations, thus impacting on the
repression of growth-promoting genes, leading to overgrowth conditions.
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