4rbo

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of a Nanog homeobox (NANOG) from Homo sapiens at 3.30 A resolution

Structural highlights

4rbo is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.3Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NANOG_HUMAN Transcription regulator involved in inner cell mass and embryonic stem (ES) cells proliferation and self-renewal. Imposes pluripotency on ES cells and prevents their differentiation towards extraembryonic endoderm and trophectoderm lineages. Blocks bone morphogenetic protein-induced mesoderm differentiation of ES cells by physically interacting with SMAD1 and interfering with the recruitment of coactivators to the active SMAD transcriptional complexes. Acts as a transcriptional activator or repressor. Binds optimally to the DNA consensus sequence 5'-TAAT[GT][GT]-3' or 5'-[CG][GA][CG]C[GC]ATTAN[GC]-3'. Binds to the POU5F1/OCT4 promoter (PubMed:25825768). Able to autorepress its expression in differentiating (ES) cells: binds to its own promoter following interaction with ZNF281/ZFP281, leading to recruitment of the NuRD complex and subsequent repression of expression. When overexpressed, promotes cells to enter into S phase and proliferation.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

NANOG (from Irish mythology Tir na nOg) transcription factor plays a central role in maintaining pluripotency, cooperating with OCT4 (also known as POU5F1 or OCT3/4), SOX2, and other pluripotency factors. Although the physiological roles of the NANOG protein have been extensively explored, biochemical and biophysical properties in relation to its structural analysis are poorly understood. Here we determined the crystal structure of the human NANOG homeodomain (hNANOG HD) bound to an OCT4 promoter DNA, which revealed amino acid residues involved in DNA recognition that are likely to be functionally important. We generated a series of hNANOG HD alanine substitution mutants based on the protein-DNA interaction and evolutionary conservation and determined their biological activities. Some mutant proteins were less stable, resulting in loss or decreased affinity for DNA binding. Overexpression of the orthologous mouse NANOG (mNANOG) mutants failed to maintain self-renewal of mouse embryonic stem cells without leukemia inhibitory factor. These results suggest that these residues are critical for NANOG transcriptional activity. Interestingly, one mutant, hNANOG L122A, conversely enhanced protein stability and DNA-binding affinity. The mNANOG L122A, when overexpressed in mouse embryonic stem cells, maintained their expression of self-renewal markers even when retinoic acid was added to forcibly drive differentiation. When overexpressed in epiblast stem cells or human induced pluripotent stem cells, the L122A mutants enhanced reprogramming into ground-state pluripotency. These findings demonstrate that structural and biophysical information on key transcriptional factors provides insights into the manipulation of stem cell behaviors and a framework for rational protein engineering.

Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells.,Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJ Proc Natl Acad Sci U S A. 2015 Mar 30. pii: 201502855. PMID:25825768^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hyslop L, Stojkovic M, Armstrong L, Walter T, Stojkovic P, Przyborski S, Herbert M, Murdoch A, Strachan T, Lako M. Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages. Stem Cells. 2005 Sep;23(8):1035-43. doi: 10.1634/stemcells.2005-0080. Epub 2005 , Jun 27. PMID:15983365 doi:http://dx.doi.org/10.1634/stemcells.2005-0080
↑ Oh JH, Do HJ, Yang HM, Moon SY, Cha KY, Chung HM, Kim JH. Identification of a putative transactivation domain in human Nanog. Exp Mol Med. 2005 Jun 30;37(3):250-4. doi: 10.1038/emm.2005.33. PMID:16000880 doi:http://dx.doi.org/10.1038/emm.2005.33
↑ Kim JS, Kim J, Kim BS, Chung HY, Lee YY, Park CS, Lee YS, Lee YH, Chung IY. Identification and functional characterization of an alternative splice variant within the fourth exon of human nanog. Exp Mol Med. 2005 Dec 31;37(6):601-7. doi: 10.1038/emm.2005.73. PMID:16391521 doi:http://dx.doi.org/10.1038/emm.2005.73
↑ Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJ. Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells. Proc Natl Acad Sci U S A. 2015 Mar 30. pii: 201502855. PMID:25825768 doi:http://dx.doi.org/10.1073/pnas.1502855112
↑ Hayashi Y, Caboni L, Das D, Yumoto F, Clayton T, Deller MC, Nguyen P, Farr CL, Chiu HJ, Miller MD, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Tomoda K, Conklin BR, Wilson IA, Yamanaka S, Fletterick RJ. Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells. Proc Natl Acad Sci U S A. 2015 Mar 30. pii: 201502855. PMID:25825768 doi:http://dx.doi.org/10.1073/pnas.1502855112

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4rbo"

Categories: Homo sapiens | Large Structures

@@ Line 1: / Line 1: @@
 ==Crystal structure of a Nanog homeobox (NANOG) from Homo sapiens at 3.30 A resolution==
-<StructureSection load='4rbo' size='340' side='right' caption='[[4rbo]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
+<StructureSection load='4rbo' size='340' side='right'caption='[[4rbo]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4rbo]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RBO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RBO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4rbo]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RBO FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NANOGP8, NM_024865 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rbo OCA], [http://pdbe.org/4rbo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rbo RCSB], [http://www.ebi.ac.uk/pdbsum/4rbo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rbo ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4rbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rbo OCA], [https://pdbe.org/4rbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rbo RCSB], [https://www.ebi.ac.uk/pdbsum/4rbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rbo ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/NANP8_HUMAN NANP8_HUMAN]] May act as a transcription regulator (By similarity). When overexpressed, promotes entry of cells into S phase and cell proliferation.
+[https://www.uniprot.org/uniprot/NANOG_HUMAN NANOG_HUMAN] Transcription regulator involved in inner cell mass and embryonic stem (ES) cells proliferation and self-renewal. Imposes pluripotency on ES cells and prevents their differentiation towards extraembryonic endoderm and trophectoderm lineages. Blocks bone morphogenetic protein-induced mesoderm differentiation of ES cells by physically interacting with SMAD1 and interfering with the recruitment of coactivators to the active SMAD transcriptional complexes. Acts as a transcriptional activator or repressor. Binds optimally to the DNA consensus sequence 5'-TAAT[GT][GT]-3' or 5'-[CG][GA][CG]C[GC]ATTAN[GC]-3'. Binds to the POU5F1/OCT4 promoter (PubMed:25825768). Able to autorepress its expression in differentiating (ES) cells: binds to its own promoter following interaction with ZNF281/ZFP281, leading to recruitment of the NuRD complex and subsequent repression of expression. When overexpressed, promotes cells to enter into S phase and proliferation.<ref>PMID:15983365</ref> <ref>PMID:16000880</ref> <ref>PMID:16391521</ref> <ref>PMID:25825768</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Structural genomic]]
+[[Category: Large Structures]]
-[[Category: STEMCELL, Partnership for Stem Cell Biology]]
-[[Category: Dna binding protein]]
-[[Category: Homeobox]]
-[[Category: Jcsg]]
-[[Category: Partnership for stem cell biology]]
-[[Category: Pf00046 family]]
-[[Category: PSI, Protein structure initiative]]
-[[Category: Psi-biology]]
-[[Category: Stemcell]]
-[[Category: Transcription]]
-[[Category: Transcription-dna complex]]

4rbo

From Proteopedia

Current revision

Crystal structure of a Nanog homeobox (NANOG) from Homo sapiens at 3.30 A resolution

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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