User:Lukáš Cakl/Sandbox 1

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(New page: ==Human PCNA mutant - S228I== <StructureSection load='5e0t' size='340' side='right' caption='5e0t, resolution 2.67&Aring;' scene=''> == Structural highlights == <table><...)
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==Human PCNA mutant - S228I==
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<StructureSection load='' size='350' side='right' caption='Human proliferating cell nuclear antigen trimer (cyan, green, deeppink) complex with p15 peptide (yellow, magenta) (PDB entry [[4d2g]])' scene='43/439961/Cv/2'>
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<StructureSection load='5e0t' size='340' side='right' caption='[[5e0t]], [[Resolution|resolution]] 2.67&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5e0t]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E0T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5E0T FirstGlance]. <br>
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</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1vym|1vym]], [[5e0v|5e0v]], [[5e0u|5e0u]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PCNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5e0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e0t OCA], [http://pdbe.org/5e0t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e0t RCSB], [http://www.ebi.ac.uk/pdbsum/5e0t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e0t ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/PCNA_HUMAN PCNA_HUMAN]] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.<ref>PMID:19443450</ref> <ref>PMID:18719106</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The eukaryotic DNA polymerase sliding clamp, proliferating cell nuclear antigen or PCNA, is a ring-shaped protein complex that surrounds DNA to act as a sliding platform for increasing processivity of cellular replicases and for coordinating various cellular pathways with DNA replication. A single point mutation, Ser228Ile, in the human PCNA gene was recently identified to cause a disease whose symptoms resemble those of DNA damage and repair disorders. The mutation lies near the binding site for most PCNA-interacting proteins. However, the structural consequences of the S228I mutation are unknown. Here, we describe the structure of the disease-causing variant, which reveals a large conformational change that dramatically transforms the binding pocket for PCNA client proteins. We show that the mutation markedly alters the binding energetics for some client proteins, while another, p21(CIP1), is only mildly affected. Structures of the disease variant bound to peptides derived from two PCNA partner proteins reveal that the binding pocket can adjust conformation to accommodate some ligands, indicating that the binding site is dynamic and pliable. Our work has implications for the plasticity of the binding site in PCNA and reveals how a disease mutation selectively alters interactions to a promiscuous binding site that is critical for DNA metabolism.
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A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site.,Duffy CM, Hilbert BJ, Kelch BA J Mol Biol. 2016 Mar 27;428(6):1023-40. doi: 10.1016/j.jmb.2015.11.029. Epub 2015, Dec 11. PMID:26688547<ref>PMID:26688547</ref>
 
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
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</div>
 
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<div class="pdbe-citations 5e0t" style="background-color:#fffaf0;"></div>
 
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== References ==
 
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<references/>
 
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__TOC__
 
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</StructureSection>
 
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[[Category: Human]]
 
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[[Category: Duffy, C M]]
 
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[[Category: Hilbert, B J]]
 
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[[Category: Kelch, B A]]
 
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[[Category: Dna binding protein]]
 
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[[Category: Dna replication]]
 
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<StructureSection load='' size='350' side='right' caption='Human proliferating cell nuclear antigen trimer (cyan, green, deeppink) complex with p15 peptide (yellow, magenta) (PDB entry [[4d2g]])' scene='43/439961/Cv/2'>
 
== Function ==
== Function ==
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[[Proliferating Cell Nuclear Antigen]] (PCNA) acts as a DNA sliding clamp by encircling the DNA and linking it to the genome. It is a processivity factor for DNA polymerase (Dpo) δ in eukaryotic cells<ref>PMID:12829735</ref>.
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[[Proliferating Cell Nuclear Antigen]] (PCNA) is a protein that acts as a DNA sliding clamp. It forms a homotrimer encircling the DNA and binds other peptides means known as [[PCNA interacting proteins]] (PIPs). It acts as a processivity factor for DNA polymerases and other enzymes which act upon DNA. Examples of such are DNA polymerase (Dpo) δ in eukaryotic cells<ref>PMID:26688547</ref>. The increases in processivity are very pronounced. The number of basepairs processed before complex dissociation occurs is increased more than a thousandfold (~10bp<ref>PMID:7040370</ref> to ~80kbp<ref>PMID:19666586</ref>) and the speed of nucleotide incorporation rises about a hundredfold <ref>PMID:17707226</ref>.
== Relevance ==
== Relevance ==
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PCNA is featured in many cellular pathways involving DNA. [FEN1] bound to PCNA acts as a flap endonuclease and cleaves a displaced ssDNA (flap) containing oxidatively damaged dideoxyribose residue <ref>PMID:10559261</ref>. As stated above PCNA is also vital to formation of the procesive complex for DNA replication <ref>PMID:1974050</ref> and is featured even in gene expression and transcription when bound to [GADD45A] <ref>PMID:20460379</ref>. Thus PCNA is relevant in research and even medicine.
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PCNA is useful in the diagnosis of high-grade dysplasia<ref>PMID:8781908</ref>.
PCNA is useful in the diagnosis of high-grade dysplasia<ref>PMID:8781908</ref>.
== Structural highlights ==
== Structural highlights ==
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p15 regulates DNA replication and repair by binding to PCNA. PCNA-p15 peptide complex shows the <scene name='43/439961/Cv/5'>peptide passes through the PCNA ring</scene> and has <scene name='43/439961/Cv/6'>numerous interactions with it</scene><ref>PMID:25762514</ref>.
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p15 regulates DNA replication and repair by binding to PCNA. PCNA-p15 peptide complex shows the <scene name='43/439961/Cv/5'>peptide passes through the PCNA ring</scene> and has <scene name='43/439961/Cv/6'>numerous interactions with it</scene><ref>PMID:25762514</ref>. Of interest is the binding site contained at each face of the PCNA ring. Said site is formed by a C-terminal domain formed groove and an interdomain connecting loop (IDCL). Some partners do bind to the N-terminal domain as well. There are multiple PIP binding motifs, but the most common one is QxxΨxx∇∇ (where Ψ is a hydrophobic residue and ∇ is either the aromatic residue F or Y) <ref>DOI:10.1016/S0092-8674(00)81347-1</ref><ref>DOI:10.1016/j.str.2004.09.018</ref>
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TODO: 1vym
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TODO: Known mutation and disease
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TODO: Known mutation structure comparison
== 3D Structures of Proliferating Cell Nuclear Antigen ==
== 3D Structures of Proliferating Cell Nuclear Antigen ==
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<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]
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==Your Heading Here (maybe something like 'Structure')==
 
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<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
 
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This is a default text for your page '''Lukáš Cakl/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
 
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
 
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== Function ==
 
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== Disease ==
 
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== Relevance ==
 
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== Structural highlights ==
 
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
 
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</StructureSection>
 
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== References ==
 
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<references/>
 

Revision as of 13:41, 29 April 2020

Human proliferating cell nuclear antigen trimer (cyan, green, deeppink) complex with p15 peptide (yellow, magenta) (PDB entry 4d2g)

Drag the structure with the mouse to rotate

References

  1. ↑ Duffy CM, Hilbert BJ, Kelch BA. A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site. J Mol Biol. 2016 Mar 27;428(6):1023-40. doi: 10.1016/j.jmb.2015.11.029. Epub 2015, Dec 11. PMID:26688547 doi:http://dx.doi.org/10.1016/j.jmb.2015.11.029
  2. ↑ Fay PJ, Johanson KO, McHenry CS, Bambara RA. Size classes of products synthesized processively by two subassemblies of Escherichia coli DNA polymerase III holoenzyme. J Biol Chem. 1982 May 25;257(10):5692-9. PMID:7040370
  3. ↑ Yao NY, Georgescu RE, Finkelstein J, O'Donnell ME. Single-molecule analysis reveals that the lagging strand increases replisome processivity but slows replication fork progression. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13236-41. doi:, 10.1073/pnas.0906157106. Epub 2009 Aug 3. PMID:19666586 doi:http://dx.doi.org/10.1073/pnas.0906157106
  4. ↑ McInerney P, Johnson A, Katz F, O'Donnell M. Characterization of a triple DNA polymerase replisome. Mol Cell. 2007 Aug 17;27(4):527-38. doi: 10.1016/j.molcel.2007.06.019. PMID:17707226 doi:http://dx.doi.org/10.1016/j.molcel.2007.06.019
  5. ↑ Matsumoto Y, Kim K, Hurwitz J, Gary R, Levin DS, Tomkinson AE, Park MS. Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/apyrimidinic sites with purified human proteins. J Biol Chem. 1999 Nov 19;274(47):33703-8. doi: 10.1074/jbc.274.47.33703. PMID:10559261 doi:http://dx.doi.org/10.1074/jbc.274.47.33703
  6. ↑ Lee SH, Hurwitz J. Mechanism of elongation of primed DNA by DNA polymerase delta, proliferating cell nuclear antigen, and activator 1. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5672-6. doi: 10.1073/pnas.87.15.5672. PMID:1974050 doi:http://dx.doi.org/10.1073/pnas.87.15.5672
  7. ↑ Sanchez R, Pantoja-Uceda D, Prieto J, Diercks T, Marcaida MJ, Montoya G, Campos-Olivas R, Blanco FJ. Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase. J Biol Chem. 2010 Jul 16;285(29):22196-201. Epub 2010 May 11. PMID:20460379 doi:10.1074/jbc.M109.069344
  8. ↑ Kullmann F, Fadaie M, Gross V, Knuchel R, Bocker T, Steinbach P, Scholmerich J, Ruschoff J. Expression of proliferating cell nuclear antigen (PCNA) and Ki-67 in dysplasia in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 1996 Apr;8(4):371-9. PMID:8781908
  9. ↑ De Biasio A, de Opakua AI, Mortuza GB, Molina R, Cordeiro TN, Castillo F, Villate M, Merino N, Delgado S, Gil-Carton D, Luque I, Diercks T, Bernado P, Montoya G, Blanco FJ. Structure of p15(PAF)-PCNA complex and implications for clamp sliding during DNA replication and repair. Nat Commun. 2015 Mar 12;6:6439. doi: 10.1038/ncomms7439. PMID:25762514 doi:http://dx.doi.org/10.1038/ncomms7439
  10. ↑ doi: https://dx.doi.org/10.1016/S0092-8674(00)81347-1
  11. ↑ Bruning JB, Shamoo Y. Structural and thermodynamic analysis of human PCNA with peptides derived from DNA polymerase-delta p66 subunit and flap endonuclease-1. Structure. 2004 Dec;12(12):2209-19. PMID:15576034 doi:http://dx.doi.org/10.1016/j.str.2004.09.018

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