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| | ==Isoform-specific inhibition of SUMO-dependent protein-protein interactions== | | ==Isoform-specific inhibition of SUMO-dependent protein-protein interactions== |
| - | <StructureSection load='5elu' size='340' side='right' caption='[[5elu]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='5elu' size='340' side='right'caption='[[5elu]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5elu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ELU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ELU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5elu]] is a 2 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=5ELU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ELU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.35Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PHYTOCYSTATIN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=32630 SYNTHETIC CONSTRUCT sequences]), SUMO2, SMT3B, SMT3H2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5elu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5elu OCA], [http://pdbe.org/5elu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5elu RCSB], [http://www.ebi.ac.uk/pdbsum/5elu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5elu ProSAT]</span></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=5elu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5elu OCA], [https://pdbe.org/5elu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5elu RCSB], [https://www.ebi.ac.uk/pdbsum/5elu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5elu ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SUMO2_HUMAN SUMO2_HUMAN]] Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins.<ref>PMID:9556629</ref> <ref>PMID:18538659</ref> <ref>PMID:18408734</ref> | + | [https://www.uniprot.org/uniprot/SUMO2_HUMAN SUMO2_HUMAN] Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins.<ref>PMID:9556629</ref> <ref>PMID:18538659</ref> <ref>PMID:18408734</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[SUMO|SUMO]] | + | *[[SUMO 3D Structures|SUMO 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Synthetic construct sequences]] | + | [[Category: Large Structures]] |
| - | [[Category: Edwards, T A]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Hall, N]] | + | [[Category: Edwards TA]] |
| - | [[Category: Howell, G]] | + | [[Category: Hall N]] |
| - | [[Category: Hughes, D J]] | + | [[Category: Howell G]] |
| - | [[Category: Mandal, U]] | + | [[Category: Hughes DJ]] |
| - | [[Category: McPherson, M J]] | + | [[Category: Mandal U]] |
| - | [[Category: Tang, A A.S]] | + | [[Category: McPherson MJ]] |
| - | [[Category: Tiede, C]] | + | [[Category: Tang AAS]] |
| - | [[Category: Tomlinson, D C]] | + | [[Category: Tiede C]] |
| - | [[Category: Trinh, C H]] | + | [[Category: Tomlinson DC]] |
| - | [[Category: Whitehouse, A]] | + | [[Category: Trinh CH]] |
| - | [[Category: Zajac, K]] | + | [[Category: Whitehouse A]] |
| - | [[Category: Signaling protein]]
| + | [[Category: Zajac K]] |
| - | [[Category: Sumoylation]]
| + | |
| - | [[Category: Ubiquitin]]
| + | |
| Structural highlights
Function
SUMO2_HUMAN Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins.[1] [2] [3]
Publication Abstract from PubMed
Because protein-protein interactions underpin most biological processes, developing tools that target them to understand their function or to inform the development of therapeutics is an important task. SUMOylation is the posttranslational covalent attachment of proteins in the SUMO family (SUMO-1, SUMO-2, or SUMO-3), and it regulates numerous cellular pathways. SUMOylated proteins are recognized by proteins with SUMO-interaction motifs (SIMs) that facilitate noncovalent interactions with SUMO. We describe the use of the Affimer system of peptide display for the rapid isolation of synthetic binding proteins that inhibit SUMO-dependent protein-protein interactions mediated by SIMs both in vitro and in cells. Crucially, these synthetic proteins did not prevent SUMO conjugation either in vitro or in cell-based systems, enabling the specific analysis of SUMO-mediated protein-protein interactions. Furthermore, through structural analysis and molecular modeling, we explored the molecular mechanisms that may underlie their specificity in interfering with either SUMO-1-mediated interactions or interactions mediated by either SUMO-2 or SUMO-3. Not only will these reagents enable investigation of the biological roles of SUMOylation, but the Affimer technology used to generate these synthetic binding proteins could also be exploited to design or validate reagents or therapeutics that target other protein-protein interactions.
Generation of specific inhibitors of SUMO-1- and SUMO-2/3-mediated protein-protein interactions using Affimer (Adhiron) technology.,Hughes DJ, Tiede C, Penswick N, Tang AA, Trinh CH, Mandal U, Zajac KZ, Gaule T, Howell G, Edwards TA, Duan J, Feyfant E, McPherson MJ, Tomlinson DC, Whitehouse A Sci Signal. 2017 Nov 14;10(505). pii: 10/505/eaaj2005. doi:, 10.1126/scisignal.aaj2005. PMID:29138295[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 1998 May 1;273(18):11349-53. PMID:9556629
- ↑ Meulmeester E, Kunze M, Hsiao HH, Urlaub H, Melchior F. Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. Mol Cell. 2008 Jun 6;30(5):610-9. doi: 10.1016/j.molcel.2008.03.021. PMID:18538659 doi:10.1016/j.molcel.2008.03.021
- ↑ Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, Palvimo JJ, Hay RT. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13. PMID:18408734 doi:10.1038/ncb1716
- ↑ Hughes DJ, Tiede C, Penswick N, Tang AA, Trinh CH, Mandal U, Zajac KZ, Gaule T, Howell G, Edwards TA, Duan J, Feyfant E, McPherson MJ, Tomlinson DC, Whitehouse A. Generation of specific inhibitors of SUMO-1- and SUMO-2/3-mediated protein-protein interactions using Affimer (Adhiron) technology. Sci Signal. 2017 Nov 14;10(505). pii: 10/505/eaaj2005. doi:, 10.1126/scisignal.aaj2005. PMID:29138295 doi:http://dx.doi.org/10.1126/scisignal.aaj2005
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