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==HMGB1-facilitated p53 DNA binding occurs via HMG-box/p53 transactivation domain interaction and is regulated by the acidic tail==
==HMGB1-facilitated p53 DNA binding occurs via HMG-box/p53 transactivation domain interaction and is regulated by the acidic tail==
<StructureSection load='2ly4' size='340' side='right'caption='[[2ly4]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
<StructureSection load='2ly4' size='340' side='right'caption='[[2ly4]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2ly4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LY4 FirstGlance]. <br>
<table><tr><td colspan='2'>[[2ly4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LY4 FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HMG1, HMGB1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), P53, TP53 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
</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=2ly4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ly4 OCA], [https://pdbe.org/2ly4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ly4 RCSB], [https://www.ebi.ac.uk/pdbsum/2ly4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ly4 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=2ly4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ly4 OCA], [https://pdbe.org/2ly4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ly4 RCSB], [https://www.ebi.ac.uk/pdbsum/2ly4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ly4 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.  Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:[https://omim.org/entry/133239 133239]].  Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:[https://omim.org/entry/151623 151623]]. LFS is an autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.<ref>PMID:10570149</ref> <ref>PMID:1933902</ref> <ref>PMID:1978757</ref> <ref>PMID:2259385</ref> <ref>PMID:1737852</ref> <ref>PMID:1565144</ref> <ref>PMID:7887414</ref> <ref>PMID:8825920</ref> <ref>PMID:9452042</ref> <ref>PMID:10484981</ref>  Defects in TP53 are involved in head and neck squamous cell carcinomas (HNSCC) [MIM:[https://omim.org/entry/275355 275355]]; also known as squamous cell carcinoma of the head and neck.  Defects in TP53 are a cause of lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.  Defects in TP53 are a cause of choroid plexus papilloma (CPLPA) [MIM:[https://omim.org/entry/260500 260500]]. Choroid plexus papilloma is a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of cerebrospinal fluid. If it undergoes malignant transformation it is called a choroid plexus carcinoma. Primary choroid plexus tumors are rare and usually occur in early childhood.<ref>PMID:12085209</ref>  Defects in TP53 are a cause of adrenocortical carcinoma (ADCC) [MIM:[https://omim.org/entry/202300 202300]]. ADCC is a rare childhood tumor of the adrenal cortex. It occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome and is a component tumor in Li-Fraumeni syndrome.<ref>PMID:11481490</ref>  Defects in TP53 are the cause of susceptibility to basal cell carcinoma 7 (BCC7) [MIM:[https://omim.org/entry/614740 614740]]. A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter.<ref>PMID:21946351</ref> 
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/HMGB1_HUMAN HMGB1_HUMAN]] DNA binding proteins that associates with chromatin and has the ability to bend DNA. Binds preferentially single-stranded DNA. Involved in V(D)J recombination by acting as a cofactor of the RAG complex. Acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS). Heparin-binding protein that has a role in the extension of neurite-type cytoplasmic processes in developing cells (By similarity). [[https://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; te function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis.<ref>PMID:9840937</ref> <ref>PMID:11025664</ref> <ref>PMID:12810724</ref> <ref>PMID:15186775</ref> <ref>PMID:15340061</ref> <ref>PMID:17317671</ref> <ref>PMID:17349958</ref> <ref>PMID:19556538</ref> <ref>PMID:20673990</ref> <ref>PMID:20959462</ref> <ref>PMID:22726440</ref> 
[https://www.uniprot.org/uniprot/HMGB1_HUMAN HMGB1_HUMAN] DNA binding proteins that associates with chromatin and has the ability to bend DNA. Binds preferentially single-stranded DNA. Involved in V(D)J recombination by acting as a cofactor of the RAG complex. Acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS). Heparin-binding protein that has a role in the extension of neurite-type cytoplasmic processes in developing cells (By similarity).
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Rowell, J P]]
[[Category: Rowell JP]]
[[Category: Simpson, K L]]
[[Category: Simpson KL]]
[[Category: Stott, K]]
[[Category: Stott K]]
[[Category: Thomas, J O]]
[[Category: Thomas JO]]
[[Category: Watson, M]]
[[Category: Watson M]]
[[Category: Hmg]]
[[Category: Nuclear protein-antitumour protein complex]]
[[Category: P53]]
[[Category: Tad]]

Revision as of 16:18, 22 February 2023

HMGB1-facilitated p53 DNA binding occurs via HMG-box/p53 transactivation domain interaction and is regulated by the acidic tailHMGB1-facilitated p53 DNA binding occurs via HMG-box/p53 transactivation domain interaction and is regulated by the acidic tail

Structural highlights

2ly4 is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HMGB1_HUMAN DNA binding proteins that associates with chromatin and has the ability to bend DNA. Binds preferentially single-stranded DNA. Involved in V(D)J recombination by acting as a cofactor of the RAG complex. Acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS). Heparin-binding protein that has a role in the extension of neurite-type cytoplasmic processes in developing cells (By similarity).

Publication Abstract from PubMed

Facilitated binding of p53 to DNA by high mobility group B1 (HMGB1) may involve interaction between the N-terminal region of p53 and the high mobility group (HMG) boxes, as well as HMG-induced bending of the DNA. Intramolecular shielding of the boxes by the HMGB1 acidic tail results in an unstable complex with p53 until the tail is truncated to half its length, at which point the A box, proposed to be the preferred binding site for p53(1-93), is exposed, leaving the B box to bind and bend DNA. The A box interacts with residues 38-61 (TAD2) of the p53 transactivation domain. Residues 19-26 (TAD1) bind weakly, but only in the context of p53(1-93) and not as a free TAD1 peptide. We have solved the structure of the A-box/p53(1-93) complex by nuclear magnetic resonance spectroscopy. The incipient amphipathic helix in TAD2 recognizes the concave DNA-binding face of the A box and may be acting as a single-stranded DNA mimic.

HMGB1-Facilitated p53 DNA Binding Occurs via HMG-Box/p53 Transactivation Domain Interaction, Regulated by the Acidic Tail.,Rowell JP, Simpson KL, Stott K, Watson M, Thomas JO Structure. 2012 Dec 5;20(12):2014-24. doi: 10.1016/j.str.2012.09.004. Epub 2012, Oct 11. PMID:23063560[1]

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

See Also

References

  1. ↑ Rowell JP, Simpson KL, Stott K, Watson M, Thomas JO. HMGB1-Facilitated p53 DNA Binding Occurs via HMG-Box/p53 Transactivation Domain Interaction, Regulated by the Acidic Tail. Structure. 2012 Dec 5;20(12):2014-24. doi: 10.1016/j.str.2012.09.004. Epub 2012, Oct 11. PMID:23063560 doi:http://dx.doi.org/10.1016/j.str.2012.09.004
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