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一种新型非经典PIP框介导PARG与PCNA的相互作用。

A novel non-canonical PIP-box mediates PARG interaction with PCNA.

作者信息

Kaufmann Tanja, Grishkovskaya Irina, Polyansky Anton A, Kostrhon Sebastian, Kukolj Eva, Olek Karin M, Herbert Sebastien, Beltzung Etienne, Mechtler Karl, Peterbauer Thomas, Gotzmann Josef, Zhang Lijuan, Hartl Markus, Zagrovic Bojan, Elsayad Kareem, Djinovic-Carugo Kristina, Slade Dea

机构信息

Department of Biochemistry, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria.

Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, 1030 Vienna, Austria.

出版信息

Nucleic Acids Res. 2017 Sep 19;45(16):9741-9759. doi: 10.1093/nar/gkx604.

DOI:10.1093/nar/gkx604
PMID:28934471
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5766153/
Abstract

Poly(ADP-ribose) glycohydrolase (PARG) regulates cellular poly(ADP-ribose) (PAR) levels by rapidly cleaving glycosidic bonds between ADP-ribose units. PARG interacts with proliferating cell nuclear antigen (PCNA) and is strongly recruited to DNA damage sites in a PAR- and PCNA-dependent fashion. Here we identified PARG acetylation site K409 that is essential for its interaction with PCNA, its localization within replication foci and its recruitment to DNA damage sites. We found K409 to be part of a non-canonical PIP-box within the PARG disordered regulatory region. The previously identified putative N-terminal PIP-box does not bind PCNA directly but contributes to PARG localization within replication foci. X-ray structure and MD simulations reveal that the PARG non-canonical PIP-box binds PCNA in a manner similar to other canonical PIP-boxes and may represent a new type of PIP-box. While the binding of previously described PIP-boxes is based on hydrophobic interactions, PARG PIP-box binds PCNA via both stabilizing hydrophobic and fine-tuning electrostatic interactions. Our data explain the mechanism of PARG-PCNA interaction through a new PARG PIP-box that exhibits non-canonical sequence properties but a canonical mode of PCNA binding.

摘要

聚（ADP-核糖）糖水解酶（PARG）通过快速切割ADP-核糖单元之间的糖苷键来调节细胞内聚（ADP-核糖）（PAR）水平。PARG与增殖细胞核抗原（PCNA）相互作用，并以PAR和PCNA依赖的方式被强烈招募到DNA损伤位点。在这里，我们鉴定出PARG乙酰化位点K409，它对于PARG与PCNA的相互作用、其在复制焦点内的定位以及其被招募到DNA损伤位点至关重要。我们发现K409是PARG无序调节区域内一个非经典PIP-box的一部分。先前鉴定的假定N端PIP-box并不直接结合PCNA，但有助于PARG在复制焦点内的定位。X射线结构和分子动力学模拟表明，PARG非经典PIP-box以类似于其他经典PIP-box的方式结合PCNA，可能代表一种新型的PIP-box。虽然先前描述的PIP-box的结合基于疏水相互作用，但PARG PIP-box通过稳定的疏水相互作用和微调的静电相互作用结合PCNA。我们的数据通过一个新的PARG PIP-box解释了PARG-PCNA相互作用的机制，该PIP-box具有非经典的序列特性，但具有经典的PCNA结合模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/1d6cbe27008c/gkx604fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/c2d996b1a00a/gkx604fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/3ab2f56e5e78/gkx604fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/a310f46f3021/gkx604fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/ef5288e89298/gkx604fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/5da2e7a03bf5/gkx604fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/530f99d79fff/gkx604fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/fd749944944d/gkx604fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/19be4336ca1e/gkx604fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/ac3f611774b5/gkx604fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/1d6cbe27008c/gkx604fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/c2d996b1a00a/gkx604fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/3ab2f56e5e78/gkx604fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/a310f46f3021/gkx604fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/ef5288e89298/gkx604fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/5da2e7a03bf5/gkx604fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/530f99d79fff/gkx604fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/fd749944944d/gkx604fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/19be4336ca1e/gkx604fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/ac3f611774b5/gkx604fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d4b/5766153/1d6cbe27008c/gkx604fig10.jpg

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Semin Cell Dev Biol. 2017 Mar;63:114-122. doi: 10.1016/j.semcdb.2016.09.010. Epub 2016 Sep 28.
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Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation.
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