1bfs: Difference between revisions

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OCA

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-[[Image:1bfs.gif|left|200px]]<br /><applet load="1bfs" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1bfs, resolution 2.2&Aring;" />
-'''STRUCTURE OF NF-KB P50 HOMODIMER BOUND TO A KB SITE'''<br />
-==Overview==
+==STRUCTURE OF NF-KB P50 HOMODIMER BOUND TO A KB SITE==
-BACKGROUND: Members of the rel/NFkappaB family of transcription factors, play a vital role in the regulation of rapid cellular responses, such as, those required to fight infection or react to cellular stress. Members of, this family of proteins form homo- and heterodimers with differing, affinities for dimerization. They share a structural motif known as the, rel homology region (RHR), the C-terminal one third of which mediates, protein dimerization. Crystal structures of the rel/NFkappaB family, members p50 and p65 in their DNA-bound homodimeric form have been solved., These structures showed that the residues from the dimerization domains of, both p50 and p65 participate in DNA binding and that the DNA-protein and, protein dimerization surfaces form one continuous overlapping interface., We desired to investigate the contribution of DNA to NFkappaB dimerization, and to identify the mechanism for the selective association of, rel/NFkappaB family peptides into transcriptionally active dimers., RESULTS: We report here the crystal structures of the dimerization domains, of murine p50 and p65 at 2.2 A and 2.0 A resolution, respectively. A, comparison of these two structures suggests that conservative amino acid, changes at three positions are responsible for the differences in their, dimer interfaces. The presence of the target DNA does not change the dimer, interface of either protein in any significant manner. CONCLUSIONS: These, two structures suggest that the rel/NFkappaB family of transcription, factors use only a few conservative changes in their amino acid sequences, to form a host of dimers with varying affinities for dimerization. Amino, acids at positions corresponding to 254, 267, and 307 of murine p50, function as primary determinants for the observed differences in, dimerization affinity. The DNA-contacting charged amino acid sidechains, from the dimerization domains are held in a similar conformation in both, the DNA-bound and free states, therefore, no major structural, rearrangement is required to bring these residues into contact with the, DNA.
+<StructureSection load='1bfs' size='340' side='right'caption='[[1bfs]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1bfs]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BFS FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</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=1bfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bfs OCA], [https://pdbe.org/1bfs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bfs RCSB], [https://www.ebi.ac.uk/pdbsum/1bfs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bfs ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/NFKB1_MOUSE NFKB1_MOUSE] NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. Plays a role in the regulation of apoptosis. Isoform 5, isoform 6 and isoform 7 act as inhibitors of transactivation of p50 NF-kappa-B subunit, probably by sequestering it in the cytoplasm. Isoform 3 (p98) (but not p84 or p105) acts as a transactivator of NF-kappa-B-regulated gene expression. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bf/1bfs_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1bfs ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-BFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1BFS OCA].
+*[[NF-kB|NF-kB]]
+__TOC__
-==Reference==
+</StructureSection>
-The role of DNA in the mechanism of NFkappaB dimer formation: crystal structures of the dimerization domains of the p50 and p65 subunits., Huang DB, Huxford T, Chen YQ, Ghosh G, Structure. 1997 Nov 15;5(11):1427-36. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9384558 9384558]
+[[Category: Large Structures]]
 [[Category: Mus musculus]]
-[[Category: Single protein]]
+[[Category: Chen YQ]]
-[[Category: Chen, Y.Q.]]
+[[Category: Ghosh G]]
-[[Category: Ghosh, G.]]
+[[Category: Huang DB]]
-[[Category: Huang, D.B.]]
+[[Category: Huxford T]]
-[[Category: Huxford, T.]]
-[[Category: dimerization domain]]
-[[Category: nf-kb]]
-[[Category: transcription factor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 11:36:56 2007''