User:Lukáš Cakl/Sandbox 1

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== 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>. 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> <scene name='84/842997/Pip_binding_pocket/1'>PIP binding pocket</scene>
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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> <scene name='84/842997/Pip_binding_pocket/1'>PIP binding pocket IDCL</scene>
== Known mutations ==
== Known mutations ==
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//TODO: Ze článku
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=== S228I ===
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S228I
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A disease causing variant in human, which causes a large conformational change of the PIP binding pocket. While the overal structure of the S228I mutant is mostly similar to the wild type, the change causes displacements extending from the mutation site, which affect the IDCL. Notably Tyr133, a highly conservated residue, rotates outwards by nearly 90° to prevent spherical conflicts with Ile228. The changes cause the binding cavity of S228I to be about a third of the size of its wild type equivalent and makes it incompetent for PIP binding. Such changes, if they were permanent, would however be lethal, as the removal of PCNA-FEN1 interactions is lethal on its own <ref>DOI:10.1158/0008-5472.CAN-08-0168</ref>. While some client proteins (e.q. [[p21<sup>CIP1</sup>]]) are left relatively unaffected even in this state, others' binding energetics are hugely disrupted (e.q. [[RNase H2B]] or [[FEN1]]). The explaination for survival of an individual carrying this mutation is sufficient malleability of IDCL (and thus of PCNA itself). Thus a PIP might be able to initiate an "induced-fit". Even here the mutant is disadvantaged as the wild type has B-factors ~40% higher than the mutant. Thus the mutation negatively affects even the IDCL dynamics. <ref>PMID:26688547</ref>
== Diseases ==
== Diseases ==
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//TODO: Ze článku
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=== Symptoms resembling DNA damage and repair disorders ===
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The disease is caused by mutation S228I as cited in the above section. <ref>PMID:26688547</ref>
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//TODO: More
== 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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[[Category: Dna binding protein]]
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[[Category: Dna replication]]

Revision as of 14:56, 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
  12. ↑ Larsen E, Kleppa L, Meza TJ, Meza-Zepeda LA, Rada C, Castellanos CG, Lien GF, Nesse GJ, Neuberger MS, Laerdahl JK, William Doughty R, Klungland A. Early-onset lymphoma and extensive embryonic apoptosis in two domain-specific Fen1 mice mutants. Cancer Res. 2008 Jun 15;68(12):4571-9. doi: 10.1158/0008-5472.CAN-08-0168. PMID:18559501 doi:http://dx.doi.org/10.1158/0008-5472.CAN-08-0168
  13. ↑ 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
  14. ↑ 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

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