2a4j

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{{STRUCTURE_2a4j| PDB=2a4j | SCENE= }}
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==Solution structure of the C-terminal domain (T94-Y172) of the human centrin 2 in complex with a 17 residues peptide (P1-XPC) from xeroderma pigmentosum group C protein==
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===Solution structure of the C-terminal domain (T94-Y172) of the human centrin 2 in complex with a 17 residues peptide (P1-XPC) from xeroderma pigmentosum group C protein===
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<StructureSection load='2a4j' size='340' side='right' caption='[[2a4j]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
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{{ABSTRACT_PUBMED_16533048}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2a4j]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1t2g 1t2g]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A4J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2A4J FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cen2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a4j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2a4j RCSB], [http://www.ebi.ac.uk/pdbsum/2a4j PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/XPC_HUMAN XPC_HUMAN]] Defects in XPC are a cause of xeroderma pigmentosum complementation group C (XP-C) [MIM:[http://omim.org/entry/278720 278720]]; also known as xeroderma pigmentosum III (XP3). XP-C is a rare human autosomal recessive disease characterized by solar sensitivity, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities.<ref>PMID:19609301</ref> <ref>PMID:17682058</ref> <ref>PMID:17355181</ref> <ref>PMID:8298653</ref> <ref>PMID:10766188</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/CETN2_HUMAN CETN2_HUMAN]] Plays a fundamental role in microtubule-organizing center structure and function. Required for centriole duplication and correct spindle formation. Has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CEP110.<ref>PMID:8248209</ref> <ref>PMID:11279143</ref> <ref>PMID:12176356</ref> <ref>PMID:15964821</ref> <ref>PMID:17154534</ref> <ref>PMID:16760425</ref> Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with RAD23B appears to stabilize XPC. In vitro, stimulates DNA binding of the XPC:RAD23B dimer.<ref>PMID:8248209</ref> <ref>PMID:11279143</ref> <ref>PMID:12176356</ref> <ref>PMID:15964821</ref> <ref>PMID:17154534</ref> <ref>PMID:16760425</ref> The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair.<ref>PMID:8248209</ref> <ref>PMID:11279143</ref> <ref>PMID:12176356</ref> <ref>PMID:15964821</ref> <ref>PMID:17154534</ref> <ref>PMID:16760425</ref> [[http://www.uniprot.org/uniprot/XPC_HUMAN XPC_HUMAN]] Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex. Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides. This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity.<ref>PMID:9734359</ref> <ref>PMID:10734143</ref> <ref>PMID:10873465</ref> <ref>PMID:12509299</ref> <ref>PMID:12547395</ref> <ref>PMID:19609301</ref> <ref>PMID:19941824</ref> <ref>PMID:20649465</ref> <ref>PMID:20028083</ref> <ref>PMID:20798892</ref> The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair. In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts. XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1.<ref>PMID:9734359</ref> <ref>PMID:10734143</ref> <ref>PMID:10873465</ref> <ref>PMID:12509299</ref> <ref>PMID:12547395</ref> <ref>PMID:19609301</ref> <ref>PMID:19941824</ref> <ref>PMID:20649465</ref> <ref>PMID:20028083</ref> <ref>PMID:20798892</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a4/2a4j_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Human centrin 2 is a component of the nucleotide excision repair system, as a subunit of the heterotrimer including xeroderma pigmentosum group C protein (XPC) and hHR23B. The C-terminal domain of centrin (C-HsCen2) binds strongly a peptide from the XPC protein (P1-XPC: N(847)-R(863)). Here, we characterize the solution Ca(2+)-dependent structural and molecular features of the C-HsCen2 in complex with P1-XPC, mainly using NMR spectroscopy and molecular modeling. The N-terminal half of the peptide, organized as an alpha helix is anchored into a deep hydrophobic cavity of the protein, because of three bulky hydrophobic residues in position 1-4-8 and electrostatic contacts with the centrin helix E. Investigation of the whole centrin interactions shows that the N-terminal domain of the protein is not involved in the complex formation and is structurally independent from the peptide-bound C-terminal domain. The complex may exist in three different binding conformations corresponding to zero, one, and two Ca(2+)-bound states, which may exchange with various rates and have distinct structural stability. The various features of the intermolecular interaction presented here constitute a centrin-specific mode for the target binding.
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==Disease==
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Flexibility and plasticity of human centrin 2 binding to the xeroderma pigmentosum group C protein (XPC) from nuclear excision repair.,Yang A, Miron S, Mouawad L, Duchambon P, Blouquit Y, Craescu CT Biochemistry. 2006 Mar 21;45(11):3653-63. PMID:16533048<ref>PMID:16533048</ref>
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[[http://www.uniprot.org/uniprot/XPC_HUMAN XPC_HUMAN]] Defects in XPC are a cause of xeroderma pigmentosum complementation group C (XP-C) [MIM:[http://omim.org/entry/278720 278720]]; also known as xeroderma pigmentosum III (XP3). XP-C is a rare human autosomal recessive disease characterized by solar sensitivity, high predisposition for developing cancers on areas exposed to sunlight and, in some cases, neurological abnormalities.<ref>PMID:19609301</ref><ref>PMID:17682058</ref><ref>PMID:17355181</ref><ref>PMID:8298653</ref><ref>PMID:10766188</ref>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/CETN2_HUMAN CETN2_HUMAN]] Plays a fundamental role in microtubule-organizing center structure and function. Required for centriole duplication and correct spindle formation. Has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CEP110.<ref>PMID:8248209</ref><ref>PMID:11279143</ref><ref>PMID:12176356</ref><ref>PMID:15964821</ref><ref>PMID:17154534</ref><ref>PMID:16760425</ref> Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with RAD23B appears to stabilize XPC. In vitro, stimulates DNA binding of the XPC:RAD23B dimer.<ref>PMID:8248209</ref><ref>PMID:11279143</ref><ref>PMID:12176356</ref><ref>PMID:15964821</ref><ref>PMID:17154534</ref><ref>PMID:16760425</ref> The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair.<ref>PMID:8248209</ref><ref>PMID:11279143</ref><ref>PMID:12176356</ref><ref>PMID:15964821</ref><ref>PMID:17154534</ref><ref>PMID:16760425</ref> [[http://www.uniprot.org/uniprot/XPC_HUMAN XPC_HUMAN]] Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex. Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides. This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity.<ref>PMID:9734359</ref><ref>PMID:10734143</ref><ref>PMID:10873465</ref><ref>PMID:12509299</ref><ref>PMID:12547395</ref><ref>PMID:19609301</ref><ref>PMID:19941824</ref><ref>PMID:20649465</ref><ref>PMID:20028083</ref><ref>PMID:20798892</ref> The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair. In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts. XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1.<ref>PMID:9734359</ref><ref>PMID:10734143</ref><ref>PMID:10873465</ref><ref>PMID:12509299</ref><ref>PMID:12547395</ref><ref>PMID:19609301</ref><ref>PMID:19941824</ref><ref>PMID:20649465</ref><ref>PMID:20028083</ref><ref>PMID:20798892</ref>
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</div>
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== References ==
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==About this Structure==
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<references/>
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[[2a4j]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1t2g 1t2g]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A4J OCA].
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__TOC__
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:016533048</ref><references group="xtra"/><references/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Blouquit, Y.]]
[[Category: Blouquit, Y.]]

Revision as of 01:19, 30 September 2014

Solution structure of the C-terminal domain (T94-Y172) of the human centrin 2 in complex with a 17 residues peptide (P1-XPC) from xeroderma pigmentosum group C protein

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