7zes

From Proteopedia

(Difference between revisions)

Current revision

Human SLFN11 dimer bound to ssDNA

Structural highlights

7zes is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SLN11_HUMAN Inhibitor of DNA replication that promotes cell death in response to DNA damage (PubMed:22927417, PubMed:26658330, PubMed:29395061). Acts as a guardian of the genome by killing cells with defective replication (PubMed:29395061). Persistently blocks stressed replication forks by opening chromatin across replication initiation sites at stressed replication forks, possibly leading to unwind DNA ahead of the MCM helicase and block fork progression, ultimately leading to cell death (PubMed:29395061). Upon DNA damage, inhibits translation of ATR or ATM based on distinct codon usage without disrupting early DNA damage response signaling (PubMed:30374083). Antiviral restriction factor with manganese-dependent type II tRNA endoribonuclease (PubMed:36115853). A single tRNA molecule is bound and cleaved by the SLFN11 dimer (PubMed:36115853). Specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1) by acting as a specific inhibitor of the synthesis of retroviruses encoded proteins in a codon-usage-dependent manner (PubMed:23000900). Impairs the replication of human cytomegalovirus (HCMV) and some Flaviviruses (PubMed:35105802, PubMed:36115853). Exploits the unique viral codon bias towards A/T nucleotides (PubMed:23000900). Also acts as an interferon (IFN)-induced antiviral protein which acts as an inhibitor of retrovirus protein synthesis (PubMed:23000900).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.

Mechanistic understanding of human SLFN11.,Metzner FJ, Wenzl SJ, Kugler M, Krebs S, Hopfner KP, Lammens K Nat Commun. 2022 Sep 17;13(1):5464. doi: 10.1038/s41467-022-33123-0. PMID:36115853^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zoppoli G, Regairaz M, Leo E, Reinhold WC, Varma S, Ballestrero A, Doroshow JH, Pommier Y. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15030-5. doi:, 10.1073/pnas.1205943109. Epub 2012 Aug 27. PMID:22927417 doi:http://dx.doi.org/10.1073/pnas.1205943109
↑ Li M, Kao E, Gao X, Sandig H, Limmer K, Pavon-Eternod M, Jones TE, Landry S, Pan T, Weitzman MD, David M. Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11. Nature. 2012 Nov 1;491(7422):125-8. doi: 10.1038/nature11433. Epub 2012 Sep 23. PMID:23000900 doi:http://dx.doi.org/10.1038/nature11433
↑ Mu Y, Lou J, Srivastava M, Zhao B, Feng XH, Liu T, Chen J, Huang J. SLFN11 inhibits checkpoint maintenance and homologous recombination repair. EMBO Rep. 2016 Jan;17(1):94-109. doi: 10.15252/embr.201540964. Epub 2015 Dec 9. PMID:26658330 doi:http://dx.doi.org/10.15252/embr.201540964
↑ Murai J, Tang SW, Leo E, Baechler SA, Redon CE, Zhang H, Al Abo M, Rajapakse VN, Nakamura E, Jenkins LMM, Aladjem MI, Pommier Y. SLFN11 Blocks Stressed Replication Forks Independently of ATR. Mol Cell. 2018 Feb 1;69(3):371-384.e6. doi: 10.1016/j.molcel.2018.01.012. PMID:29395061 doi:http://dx.doi.org/10.1016/j.molcel.2018.01.012
↑ Li M, Kao E, Malone D, Gao X, Wang JYJ, David M. DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs. Nat Struct Mol Biol. 2018 Nov;25(11):1047-1058. PMID:30374083 doi:10.1038/s41594-018-0142-5
↑ Nightingale K, Potts M, Hunter LM, Fielding CA, Zerbe CM, Fletcher-Etherington A, Nobre L, Wang ECY, Strang BL, Houghton JW, Antrobus R, Suarez NM, Nichols J, Davison AJ, Stanton RJ, Weekes MP. Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A. 2022 Feb 8;119(6):e2108173119. PMID:35105802 doi:10.1073/pnas.2108173119
↑ Metzner FJ, Wenzl SJ, Kugler M, Krebs S, Hopfner KP, Lammens K. Mechanistic understanding of human SLFN11. Nat Commun. 2022 Sep 17;13(1):5464. doi: 10.1038/s41467-022-33123-0. PMID:36115853 doi:http://dx.doi.org/10.1038/s41467-022-33123-0
↑ Metzner FJ, Wenzl SJ, Kugler M, Krebs S, Hopfner KP, Lammens K. Mechanistic understanding of human SLFN11. Nat Commun. 2022 Sep 17;13(1):5464. doi: 10.1038/s41467-022-33123-0. PMID:36115853 doi:http://dx.doi.org/10.1038/s41467-022-33123-0

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7zes"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7zes]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZES FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=7zes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zes OCA], [https://pdbe.org/7zes PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zes RCSB], [https://www.ebi.ac.uk/pdbsum/7zes PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zes ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/SLN11_HUMAN SLN11_HUMAN]] Inhibitor of DNA replication that promotes cell death in response to DNA damage (PubMed:22927417, PubMed:26658330, PubMed:29395061). Acts as a guardian of the genome by killing cells with defective replication (PubMed:29395061). Persistently blocks stressed replication forks by opening chromatin across replication initiation sites at stressed replication forks, possibly leading to unwind DNA ahead of the MCM helicase and block fork progression, ultimately leading to cell death (PubMed:29395061). Acts independently of ATR (PubMed:29395061). Also acts as an interferon (IFN)-induced antiviral protein which acts as an inhibitor of retrovirus protein synthesis (PubMed:23000900). Specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1) by acting as a specific inhibitor of the synthesis of retroviruses encoded proteins in a codon-usage-dependent manner (PubMed:23000900). Binds to tRNAs and exploits the unique viral codon bias towards A/T nucleotides (PubMed:23000900). The exact inhibition mechanism is unclear: may either sequester tRNAs, prevent their maturation via post-transcriptional processing or may accelerate their deacylation (PubMed:23000900). Does not inhibit reverse transcription, integration or production and nuclear export of viral RNA (PubMed:23000900).<ref>PMID:22927417</ref> <ref>PMID:23000900</ref> <ref>PMID:26658330</ref> <ref>PMID:29395061</ref>
+[https://www.uniprot.org/uniprot/SLN11_HUMAN SLN11_HUMAN] Inhibitor of DNA replication that promotes cell death in response to DNA damage (PubMed:22927417, PubMed:26658330, PubMed:29395061). Acts as a guardian of the genome by killing cells with defective replication (PubMed:29395061). Persistently blocks stressed replication forks by opening chromatin across replication initiation sites at stressed replication forks, possibly leading to unwind DNA ahead of the MCM helicase and block fork progression, ultimately leading to cell death (PubMed:29395061). Upon DNA damage, inhibits translation of ATR or ATM based on distinct codon usage without disrupting early DNA damage response signaling (PubMed:30374083). Antiviral restriction factor with manganese-dependent type II tRNA endoribonuclease (PubMed:36115853). A single tRNA molecule is bound and cleaved by the SLFN11 dimer (PubMed:36115853). Specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1) by acting as a specific inhibitor of the synthesis of retroviruses encoded proteins in a codon-usage-dependent manner (PubMed:23000900). Impairs the replication of human cytomegalovirus (HCMV) and some Flaviviruses (PubMed:35105802, PubMed:36115853). Exploits the unique viral codon bias towards A/T nucleotides (PubMed:23000900). Also acts as an interferon (IFN)-induced antiviral protein which acts as an inhibitor of retrovirus protein synthesis (PubMed:23000900).<ref>PMID:22927417</ref> <ref>PMID:23000900</ref> <ref>PMID:26658330</ref> <ref>PMID:29395061</ref> <ref>PMID:30374083</ref> <ref>PMID:35105802</ref> <ref>PMID:36115853</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

7zes

From Proteopedia

Current revision

Human SLFN11 dimer bound to ssDNA

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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