View source for 8yyv


==A dimeric STAT1-DNA complex==
<StructureSection load='8yyv' size='340' side='right'caption='[[8yyv]], [[Resolution|resolution]] 3.07&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8yyv]] is a 3 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=8YYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YYV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.07&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></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=8yyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8yyv OCA], [https://pdbe.org/8yyv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8yyv RCSB], [https://www.ebi.ac.uk/pdbsum/8yyv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8yyv ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/STAT1_HUMAN STAT1_HUMAN] Defects in STAT1 are the cause of STAT1 deficiency complete (STAT1D) [MIM:[https://omim.org/entry/613796 613796]. STAT1D is a disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness.<ref>PMID:12590259</ref> <ref>PMID:20841510</ref>   Defects in STAT1 are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM:[https://omim.org/entry/209950 209950]; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance.<ref>PMID:11452125</ref> <ref>PMID:16934001</ref> <ref>PMID:22573496</ref>   Defects in STAT1 are the cause of familial candidiasis type 7 (CANDF7) [MIM:[https://omim.org/entry/614162 614162]. A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans. Note=STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin-17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643).<ref>PMID:21727188</ref> <ref>PMID:21714643</ref> 
== Function ==
[https://www.uniprot.org/uniprot/STAT1_HUMAN STAT1_HUMAN] Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated. It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.<ref>PMID:9724754</ref> <ref>PMID:12855578</ref> <ref>PMID:12764129</ref> <ref>PMID:15322115</ref> <ref>PMID:19088846</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Signal transducer and activator of transcription (STAT) family members mediate signaling in the Janus kinase (JAK)-STAT pathway and are activated by phosphorylation at a conserved tyrosine residue, resulting in dimerization through reciprocal interactions between the phosphotyrosine and a Src homology 2 (SH2) domain. Tyrosine-phosphorylated STAT (pY-STAT) then translocates to the nucleus to induce the expression of genes encoding antiviral proteins. Although the active and functional forms of STATs are conventionally considered to be dimers, STATs can undergo higher-order oligomerization, which is implicated in regulating transcriptional activity. We present the cryo-electron microscopy (cryo-EM) structure of the tetrameric form of intact pY-STAT1 in complex with DNA, which indicates that interactions between the amino-terminal domains (NTDs) of STAT1 induce oligomerization. The tetrameric structure revealed a compact conformation with a previously uncharacterized binding interface: Two DNA-bound dimers are twofold symmetrically aligned to transform into a tandem DNA-binding model without NTD dimer separation. Moreover, biochemical analyses indicated that the rabies virus P-protein selectively targeted tetrameric pY-STAT1. Combined with data showing which regions contribute to the interaction between pY-STAT1 and the P-protein, we constructed a binding model explaining how P recognizes the pY-STAT1 tetramer. These data provide insight into how pathogenic viruses target signaling pathways that mediate the host immune response.

Structural analysis reveals how tetrameric tyrosine-phosphorylated STAT1 is targeted by the rabies virus P-protein.,Sugiyama A, Minami M, Ugajin K, Inaba-Inoue S, Yabuno N, Takekawa Y, Xiaomei S, Takei S, Sasaki M, Nomai T, Jiang X, Kita S, Maenaka K, Hirose M, Yao M, Gooley PR, Moseley GW, Sugita Y, Ose T Sci Signal. 2025 Mar 18;18(878):eads2210. doi: 10.1126/scisignal.ads2210. Epub , 2025 Mar 18. PMID:40100957<ref>PMID:40100957</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8yyv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Minami M]]
[[Category: Ose T]]
[[Category: Sugita Y]]
[[Category: Sugiyama A]]