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==Ubiquitin specific protease 11 USP11 - peptide F complex==
==Ubiquitin specific protease 11 USP11 - peptide F complex==
<StructureSection load='5ok6' size='340' side='right' caption='[[5ok6]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
<StructureSection load='5ok6' size='340' side='right'caption='[[5ok6]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5ok6]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OK6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OK6 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5ok6]] 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=5OK6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OK6 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AAR:ARGININEAMIDE'>AAR</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AAR:ARGININEAMIDE'>AAR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mem|4mem]], [[4mel|4mel]]</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=5ok6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ok6 OCA], [https://pdbe.org/5ok6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ok6 RCSB], [https://www.ebi.ac.uk/pdbsum/5ok6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ok6 ProSAT]</span></td></tr>
<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=5ok6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ok6 OCA], [http://pdbe.org/5ok6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ok6 RCSB], [http://www.ebi.ac.uk/pdbsum/5ok6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ok6 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[https://www.uniprot.org/uniprot/UBP11_HUMAN UBP11_HUMAN] Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains. Inhibits the degradation of target proteins by the proteasome. Plays a role in the regulation of pathways leading to NF-kappa-B activation. Plays a role in the regulation of DNA repair after double-stranded DNA breaks.<ref>PMID:15314155</ref> <ref>PMID:17897950</ref> <ref>PMID:18408009</ref> <ref>PMID:19874889</ref> <ref>PMID:20233726</ref>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
The ubiquitin specific protease 11 (USP11) is implicated in DNA repair, viral RNA replication, and TGFbeta signaling. We report the first characterization of the USP11 domain architecture and its role in regulating the enzymatic activity. USP11 consists of an N-terminal "domain present in USPs" (DUSP) and "ubiquitin-like" (UBL) domain, together referred to as DU domains, and the catalytic domain harboring a second UBL domain. Crystal structures of the DU domains show a tandem arrangement with a shortened beta-hairpin at the two-domain interface and altered surface characteristics compared to the homologues USP4 and USP15. A conserved VEVY motif is a signature feature at the two-domain interface that shapes a potential protein interaction site. Small angle X-ray scattering and gel filtration experiments are consistent with the USP11DU domains and full-length USP11 being monomeric. Unexpectedly, we reveal, through kinetic assays of a series of deletion mutants, that the catalytic activity of USP11 is not regulated through intramolecular autoinhibition or activation by the N-terminal DU or UBL domains. Moreover, ubiquitin chain cleavage assays with all eight linkages reveal a preference for Lys63-, Lys6-, Lys33-, and Lys11-linked chains over Lys27-, Lys29-, and Lys48-linked and linear chains consistent with USP11's function in DNA repair pathways that is mediated by the protease domain. Our data support a model whereby USP11 domains outside the catalytic core domain serve as protein interaction or trafficking modules rather than a direct regulatory function of the proteolytic activity. This highlights the diversity of USPs in substrate recognition and regulation of ubiquitin deconjugation.
Ubiquitin-specific proteases (USPs) reverse ubiquitination and regulate virtually all cellular processes. Defined noncatalytic domains in USP4 and USP15 are known to interact with E3 ligases and substrate recruitment factors. No such interactions have been reported for these domains in the paralog USP11, a key regulator of DNA double-strand break repair by homologous recombination. We hypothesized that USP11 domains adjacent to its protease domain harbor unique peptide-binding sites. Here, using a next-generation phage display (NGPD) strategy, combining phage display library screening with next-generation sequencing, we discovered unique USP11-interacting peptide motifs. Isothermal titration calorimetry disclosed that the highest affinity peptides (KD of approximately 10 mum) exhibit exclusive selectivity for USP11 over USP4 and USP15 in vitro Furthermore, a crystal structure of a USP11-peptide complex revealed a previously unknown binding site in USP11's noncatalytic ubiquitin-like (UBL) region. This site interacted with a helical motif and is absent in USP4 and USP15. Reporter assays using USP11-WT versus a binding pocket-deficient double mutant disclosed that this binding site modulates USP11's function in homologous recombination-mediated DNA repair. The highest affinity USP11 peptide binder fused to a cellular delivery sequence induced significant nuclear localization and cell cycle arrest in S phase, affecting the viability of different mammalian cell lines. The USP11 peptide ligands and the paralog-specific functional site in USP11 identified here provide a framework for the development of new biochemical tools and therapeutic agents. We propose that an NGPD-based strategy for identifying interacting peptides may be applied also to other cellular targets.


Structure and Catalytic Regulatory Function of Ubiquitin Specific Protease 11 N-Terminal and Ubiquitin-like Domains.,Harper S, Gratton HE, Cornaciu I, Oberer M, Scott DJ, Emsley J, Dreveny I Biochemistry. 2014 Apr 29. PMID:24724799<ref>PMID:24724799</ref>
Discovery of peptide ligands targeting a specific ubiquitin-like domain-binding site in the deubiquitinase USP11.,Spiliotopoulos A, Blokpoel Ferreras L, Densham RM, Caulton SG, Maddison BC, Morris JR, Dixon JE, Gough KC, Dreveny I J Biol Chem. 2019 Jan 11;294(2):424-436. doi: 10.1074/jbc.RA118.004469. Epub 2018, Oct 29. PMID:30373771<ref>PMID:30373771</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 5ok6" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 5ok6" style="background-color:#fffaf0;"></div>
==See Also==
*[[Thioesterase 3D structures|Thioesterase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dreveny, I]]
[[Category: Homo sapiens]]
[[Category: Spiliotopoulos, A]]
[[Category: Large Structures]]
[[Category: Peptide ligand complex]]
[[Category: Synthetic construct]]
[[Category: Protease]]
[[Category: Dreveny I]]
[[Category: Protein binding]]
[[Category: Spiliotopoulos A]]
[[Category: Ubiquitin]]

Latest revision as of 19:52, 13 December 2023

Ubiquitin specific protease 11 USP11 - peptide F complexUbiquitin specific protease 11 USP11 - peptide F complex

Structural highlights

5ok6 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:X-ray diffraction, Resolution 1.3Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UBP11_HUMAN Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains. Inhibits the degradation of target proteins by the proteasome. Plays a role in the regulation of pathways leading to NF-kappa-B activation. Plays a role in the regulation of DNA repair after double-stranded DNA breaks.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

Ubiquitin-specific proteases (USPs) reverse ubiquitination and regulate virtually all cellular processes. Defined noncatalytic domains in USP4 and USP15 are known to interact with E3 ligases and substrate recruitment factors. No such interactions have been reported for these domains in the paralog USP11, a key regulator of DNA double-strand break repair by homologous recombination. We hypothesized that USP11 domains adjacent to its protease domain harbor unique peptide-binding sites. Here, using a next-generation phage display (NGPD) strategy, combining phage display library screening with next-generation sequencing, we discovered unique USP11-interacting peptide motifs. Isothermal titration calorimetry disclosed that the highest affinity peptides (KD of approximately 10 mum) exhibit exclusive selectivity for USP11 over USP4 and USP15 in vitro Furthermore, a crystal structure of a USP11-peptide complex revealed a previously unknown binding site in USP11's noncatalytic ubiquitin-like (UBL) region. This site interacted with a helical motif and is absent in USP4 and USP15. Reporter assays using USP11-WT versus a binding pocket-deficient double mutant disclosed that this binding site modulates USP11's function in homologous recombination-mediated DNA repair. The highest affinity USP11 peptide binder fused to a cellular delivery sequence induced significant nuclear localization and cell cycle arrest in S phase, affecting the viability of different mammalian cell lines. The USP11 peptide ligands and the paralog-specific functional site in USP11 identified here provide a framework for the development of new biochemical tools and therapeutic agents. We propose that an NGPD-based strategy for identifying interacting peptides may be applied also to other cellular targets.

Discovery of peptide ligands targeting a specific ubiquitin-like domain-binding site in the deubiquitinase USP11.,Spiliotopoulos A, Blokpoel Ferreras L, Densham RM, Caulton SG, Maddison BC, Morris JR, Dixon JE, Gough KC, Dreveny I J Biol Chem. 2019 Jan 11;294(2):424-436. doi: 10.1074/jbc.RA118.004469. Epub 2018, Oct 29. PMID:30373771[6]

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

See Also

References

  1. ↑ Schoenfeld AR, Apgar S, Dolios G, Wang R, Aaronson SA. BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol Cell Biol. 2004 Sep;24(17):7444-55. PMID:15314155 doi:http://dx.doi.org/10.1128/MCB.24.17.7444-7455.2004
  2. ↑ Yamaguchi T, Kimura J, Miki Y, Yoshida K. The deubiquitinating enzyme USP11 controls an IkappaB kinase alpha (IKKalpha)-p53 signaling pathway in response to tumor necrosis factor alpha (TNFalpha). J Biol Chem. 2007 Nov 23;282(47):33943-8. Epub 2007 Sep 26. PMID:17897950 doi:http://dx.doi.org/10.1074/jbc.M706282200
  3. ↑ Lin CH, Chang HS, Yu WC. USP11 stabilizes HPV-16E7 and further modulates the E7 biological activity. J Biol Chem. 2008 Jun 6;283(23):15681-8. doi: 10.1074/jbc.M708278200. Epub 2008, Apr 11. PMID:18408009 doi:http://dx.doi.org/10.1074/jbc.M708278200
  4. ↑ Sun W, Tan X, Shi Y, Xu G, Mao R, Gu X, Fan Y, Yu Y, Burlingame S, Zhang H, Rednam SP, Lu X, Zhang T, Fu S, Cao G, Qin J, Yang J. USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal. 2010 Mar;22(3):386-94. doi: 10.1016/j.cellsig.2009.10.008. Epub . PMID:19874889 doi:http://dx.doi.org/10.1016/j.cellsig.2009.10.008
  5. ↑ Wiltshire TD, Lovejoy CA, Wang T, Xia F, O'Connor MJ, Cortez D. Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol Chem. 2010 May 7;285(19):14565-71. doi: 10.1074/jbc.M110.104745. Epub 2010, Mar 15. PMID:20233726 doi:http://dx.doi.org/10.1074/jbc.M110.104745
  6. ↑ Spiliotopoulos A, Blokpoel Ferreras L, Densham RM, Caulton SG, Maddison BC, Morris JR, Dixon JE, Gough KC, Dreveny I. Discovery of peptide ligands targeting a specific ubiquitin-like domain-binding site in the deubiquitinase USP11. J Biol Chem. 2019 Jan 11;294(2):424-436. doi: 10.1074/jbc.RA118.004469. Epub 2018, Oct 29. PMID:30373771 doi:http://dx.doi.org/10.1074/jbc.RA118.004469

5ok6, resolution 1.30Å

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