PDBsum entry 2nab

Transcription

PDB id: 2nab

Contents

Protein chain

41 a.a.

Metals

_ZN

PDB id:

2nab

Name:

Transcription

Title:

Nizp1-c2hr zinc finger structure

Structure:

Zinc finger protein 496. Chain: a. Fragment: unp residue 397-434. Synonym: nsd1-interacting zinc finger protein 1, zinc finger protein with krab and scan domains 17. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: znf496, nizp11, zfp496, zkscan17. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

15 models

Authors:

A.Berardi,G.Quilici,D.Spiliotopoulos,M.Corral-Rodriguez,F.Martin, M.Degano,G.Tonon,G.Musco

Key ref:

A.Berardi et al. (2016). Structural basis for PHDVC5HCHNSD1-C2HRNizp1 interaction: implications for Sotos syndrome. Nucleic Acids Res, 44, 3448-3463. PubMed id: 26896805 DOI: 10.1093/nar/gkw103

Date:

22-Dec-15 Release date: 09-Mar-16

Protein chain

Q5SXI5  (ZN496_MOUSE) -  Zinc finger protein 496 from Mus musculus

Seq: 585 a.a.

Struc: 41 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1093/nar/gkw103

Nucleic Acids Res 44:3448-3463 (2016)

PubMed id: 26896805

Structural basis for PHDVC5HCHNSD1-C2HRNizp1 interaction: implications for Sotos syndrome.

A.Berardi, G.Quilici, D.Spiliotopoulos, M.A.Corral-Rodriguez, F.Martin-Garcia, M.Degano, G.Tonon, M.Ghitti, G.Musco.

ABSTRACT

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.