2o3c: Difference between revisions
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< | ==Crystal structure of zebrafish Ape== | ||
<StructureSection load='2o3c' size='340' side='right'caption='[[2o3c]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2o3c]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O3C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2O3C 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]] 2.3Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PB:LEAD+(II)+ION'>PB</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=2o3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2o3c OCA], [https://pdbe.org/2o3c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2o3c RCSB], [https://www.ebi.ac.uk/pdbsum/2o3c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2o3c ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/APEX1_DANRE APEX1_DANRE] Function as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Required for passage through the midblastula transition MBT. May also acts as a endoribonuclease involved in the control of single-stranded RNA metabolism. Has no redox activity. Binds DNA and RNA.<ref>PMID:16966376</ref> <ref>PMID:18579163</ref> | |||
== 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/o3/2o3c_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=2o3c ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human apurinic/apyrimidinic endonuclease (hApe1) encodes two important functional activities: an essential base excision repair (BER) activity and a redox activity that regulates expression of a number of genes through reduction of their transcription factors, AP-1, NFkappaB, HIF-1alpha, CREB, p53 and others. The BER function is highly conserved from prokaryotes (E. coli exonuclease III) to humans (hApe1). Here, we provide evidence supporting a redox function unique to mammalian Apes. An evolutionary analysis of Ape sequences reveals that, of the 7 Cys residues, Cys 93, 99, 208, 296, and 310 are conserved in both mammalian and non-mammalian vertebrate Apes, while Cys 65 is unique to mammalian Apes. In the zebrafish Ape (zApe), selected as the vertebrate sequence most distant from human, the residue equivalent to Cys 65 is Thr 58. The wild-type zApe enzyme was tested for redox activity in both in vitro EMSA and transactivation assays and found to be inactive, similar to C65A hApe1. Substitution of Thr 58 with Cys in zApe, however, resulted in a redox active enzyme, suggesting that a Cys residue in this position is indeed critical for redox function. In order to further probe differences between redox active and inactive enzymes, we have determined the crystal structures of vertebrate redox inactive enzymes, the C65A human Ape1 enzyme and the zApe enzyme at 1.9 and 2.3A, respectively. Our results provide new insights on the redox function and highlight a dramatic gain-of-function activity for Ape1 in mammals not found in non-mammalian vertebrates or lower organisms. | |||
Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease.,Georgiadis MM, Luo M, Gaur RK, Delaplane S, Li X, Kelley MR Mutat Res. 2008 Aug 25;643(1-2):54-63. Epub 2008 May 18. PMID:18579163<ref>PMID:18579163</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2o3c" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Apurinic-Apyrimidinic Endonuclease|Apurinic-Apyrimidinic Endonuclease]] | |||
*[[Apurinic/apyrimidinic endonuclease 3D structures|Apurinic/apyrimidinic endonuclease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Danio rerio]] | [[Category: Danio rerio]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Delaplane S]] | ||
[[Category: | [[Category: Gaur RK]] | ||
[[Category: | [[Category: Georgiadis MM]] | ||
[[Category: | [[Category: Svenson J]] | ||
Latest revision as of 13:29, 30 August 2023
Crystal structure of zebrafish ApeCrystal structure of zebrafish Ape
Structural highlights
FunctionAPEX1_DANRE Function as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. Required for passage through the midblastula transition MBT. May also acts as a endoribonuclease involved in the control of single-stranded RNA metabolism. Has no redox activity. Binds DNA and RNA.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHuman apurinic/apyrimidinic endonuclease (hApe1) encodes two important functional activities: an essential base excision repair (BER) activity and a redox activity that regulates expression of a number of genes through reduction of their transcription factors, AP-1, NFkappaB, HIF-1alpha, CREB, p53 and others. The BER function is highly conserved from prokaryotes (E. coli exonuclease III) to humans (hApe1). Here, we provide evidence supporting a redox function unique to mammalian Apes. An evolutionary analysis of Ape sequences reveals that, of the 7 Cys residues, Cys 93, 99, 208, 296, and 310 are conserved in both mammalian and non-mammalian vertebrate Apes, while Cys 65 is unique to mammalian Apes. In the zebrafish Ape (zApe), selected as the vertebrate sequence most distant from human, the residue equivalent to Cys 65 is Thr 58. The wild-type zApe enzyme was tested for redox activity in both in vitro EMSA and transactivation assays and found to be inactive, similar to C65A hApe1. Substitution of Thr 58 with Cys in zApe, however, resulted in a redox active enzyme, suggesting that a Cys residue in this position is indeed critical for redox function. In order to further probe differences between redox active and inactive enzymes, we have determined the crystal structures of vertebrate redox inactive enzymes, the C65A human Ape1 enzyme and the zApe enzyme at 1.9 and 2.3A, respectively. Our results provide new insights on the redox function and highlight a dramatic gain-of-function activity for Ape1 in mammals not found in non-mammalian vertebrates or lower organisms. Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease.,Georgiadis MM, Luo M, Gaur RK, Delaplane S, Li X, Kelley MR Mutat Res. 2008 Aug 25;643(1-2):54-63. Epub 2008 May 18. PMID:18579163[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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