View source for 6qcg


==PCNA complex with Cdt1 N-terminal PIP-box peptide==
<StructureSection load='6qcg' size='340' side='right'caption='[[6qcg]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6qcg]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QCG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QCG 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]] 3.4&#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=6qcg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qcg OCA], [https://pdbe.org/6qcg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qcg RCSB], [https://www.ebi.ac.uk/pdbsum/6qcg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qcg ProSAT]</span></td></tr>
</table>
== Function ==
[https://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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The CRL4(Cdt2) ubiquitin ligase complex is an essential regulator of cell-cycle progression and genome stability, ubiquitinating substrates such as p21, Set8, and Cdt1, via a display of substrate degrons on proliferating cell nuclear antigens (PCNAs). Here, we examine the hierarchy of the ligase and substrate recruitment kinetics onto PCNA at sites of DNA replication. We demonstrate that the C-terminal end of Cdt2 bears a PCNA interaction protein motif (PIP box, Cdt2(PIP)), which is necessary and sufficient for the binding of Cdt2 to PCNA. Cdt2(PIP) binds PCNA directly with high affinity, two orders of magnitude tighter than the PIP box of Cdt1. X-ray crystallographic structures of PCNA bound to Cdt2(PIP) and Cdt1(PIP) show that the peptides occupy all three binding sites of the trimeric PCNA ring. Mutating Cdt2(PIP) weakens the interaction with PCNA, rendering CRL4(Cdt2) less effective in Cdt1 ubiquitination and leading to defects in Cdt1 degradation. The molecular mechanism we present suggests a new paradigm for bringing substrates to the CRL4-type ligase, where the substrate receptor and substrates bind to a common multivalent docking platform to enable subsequent ubiquitination.

Direct binding of Cdt2 to PCNA is important for targeting the CRL4(Cdt2) E3 ligase activity to Cdt1.,Hayashi A, Giakoumakis NN, Heidebrecht T, Ishii T, Panagopoulos A, Caillat C, Takahara M, Hibbert RG, Suenaga N, Stadnik-Spiewak M, Takahashi T, Shiomi Y, Taraviras S, von Castelmur E, Lygerou Z, Perrakis A, Nishitani H Life Sci Alliance. 2018 Dec 31;1(6):e201800238. doi: 10.26508/lsa.201800238. , eCollection 2018 Dec. PMID:30623174<ref>PMID:30623174</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6qcg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Proliferating cell nuclear antigen 3D structures|Proliferating cell nuclear antigen 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Perrakis A]]
[[Category: Von Castelmur E]]