Ubiquitin protein ligase

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<StructureSection load='' size='350' side='right' caption='Human UPL HOIP (magenta) complex with ubiquitin (green), imidazole and Zn+2 ion (grey) [[4ljo]]' scene='53/537519/Cv/1' >
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[[Image:1c4z.png|left|200px|thumb|Crystal structure of Human UPL catalytic domain trimer (grey, green, pink) complex with ubiquitin conjugating enzyme E2 (yellow), [1c4z]]]]
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== Function ==
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{{STRUCTURE_1c4z| PDB=1c4z | SIZE=400| SCENE= |right|CAPTION=Human UPL catalytic domain complex with ubiquitin conjugating enzyme E2 [[1c4z]] }}
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'''Ubiquitin-protein ligase''' (UPL) ('''E3''') or '''E3 ubiquitin-protein ligase''' in combination with ubiquitin-conjugating enzyme (E2) causes the attachment of ubiquitin to lysine in a target protein<ref>PMID:16250895</ref>.
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*'''UPL XIAP''' or '''X-linked Inhibitor of Apoptosis Protein''' stops apoptosis induced by viral infection or by overproduction of caspases. UPL XIAP binds caspase-3, -7 and -9<ref>PMID:17549347</ref>. UPL XIAP is inhibited by Smac – a death signaling protein.
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*'''RING-type E3 ubiquitin transferase''' are E3s which do not have Zn+2 coordination<ref>PMID:23747565</ref>.
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*'''HOIL-1''' or '''RanBP-type and C3HC4-type zinc finger-containing protein 1''' is an atypical E3 ligase which forms ester bonds between ubiquitin and Ser/Thr residues in proteins<ref>PMID:33932090</ref>.
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*'''NEDD4-like Ubiquitin protein ligase WWP''' see [[WWP2]].
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Examples of E3 ubiquitin-protein ligases include [[Parkin]]
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== Disease ==
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XIAP mutations cause X-linked lymphoproliferative syndrome type 2<ref>PMID:24942515</ref>. Parkin UPL has a direct causal role in neurodegenerative disorders<ref>PMID:16908979</ref>. Cereblon nonsense mutation causes autosomal recessive nonsyndromic mental retardation<ref>PMID:23983124</ref>.
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== Relevance ==
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Overexpression of UPL XIAP functions as tumor marker. UPL '''cereblon''' is inhibited by thalidomide<ref>PMID:24292623</ref> and [[Lenalidomide]].
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== Structural highlights ==
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UPL can contain several distinct domains like:<br />
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* '''WW''' domains which contain 2 tryptophans which bind proline-rich peptide;<br />
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* '''UBA''' – Ubiquitin-Associated Domain;<br />
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* '''TKB''' – Tyrosine Kinase Binding domain;<br />
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* '''C2''' – an 8 β strand domain which coordinates targeting proteins toward cell membrane;<br />
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* '''Cereblon''' is a target for thalidomide;<br />
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* '''HECT''' – Homologous to the E6-AP C-terminus;<br />
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* '''RING''' – Really Intersting New Gene involved in binding to E2;<br />
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* '''FHA''' – Forkhead Associated domain recognizing phosphothreonine;<br />
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* '''IBR''' – involved in binding to E2;<br />
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* '''PHD''' finger – Plant Homeo Domain is 50-80 amino acid long which contains a CHC motif;<br />
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* '''SRA – SET and RING-Associated''' domain;<br />
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* '''TUDOR''' – a ca. 50 amino acids long and recognizes dimethylated arginine;<br />
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* '''CPH''' – protein-protein interaction domain;<br />
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* '''UBR''' – a ca. 70 amino acid long zinc finger-like domain;<br />
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* '''CUE''' – a ubiquitin-binding domain.<br />
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'''UPL XIAP''' consists of 3 BIR (baculoviral IAP repeat) domains, followed by UBA (ubiquitin-binding) domain and RING (C-terminal RING finger) domain. BIR2 inhibits caspase-3 and -7. BIR3 inhibits caspase-9.
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UPL contains an thioester-forming cysteine which catalyzes the transfer of ubiquitin from E2 to a substrate lysine. The surface interacting residues of UPL and the acceptor ubiquitin are shown here<ref>PMID:24141947</ref>.
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*<scene name='53/537519/Cv/8'>Ubiquitin/protein ligase interface shown in space-filled representation</scene>.
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*<scene name='53/537519/Cv/10'>Ubiquitin/protein ligase interface interactions</scene>.
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*<scene name='53/537519/Cv/9'>1st Zn coordination site</scene>.
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*<scene name='53/537519/Cv/11'>2nd Zn coordination site</scene>.
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*<scene name='53/537519/Cv/12'>3rd Zn coordination site</scene>.
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*<scene name='53/537519/Cv/13'>4th Zn coordination site</scene>.
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For some details see<br />
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*[[TIR1 ubiquitin ligase]]<br />
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*[[Herbicide 2,4-D bound to TIR1 Ubiquitin Ligase]].
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'''Ubiquitin-protein ligase''' (UPL) in combination with ubiquitin-conjugating enzyme (E2) causes the attachment of ubiquitin to lysine to a target protein. UPL can contain several distinct domains like: WW domains which contains 2 tryptophans which bind proline-rich peptide; UBA – Ubiquitin-Associated Domain; TKB – Tyrosine Kinase Binding domain; C2 – an 8 β strand domain which coordinates targeting proteins toward cell membrane; HECT – Homologous to the E6-AP Carboxyl Terminus; RING – Really Intersting New Gene involved in binding to E2; FHA – Forkhead Associated domain recognizing phosphothreonine; IBR – involved in binding to E2; PHD finger – Plant Homeo Domain is 50-80 amino acid long which contains a CHC motif; SRA – SET and RING-Associated domain; TUDOR – is a ca. 50 amino acids long and recognizes dimethylated arginine; CPH – protein-protein interaction domain; UBR – a ca. 70 amino acid long zinc finger-like domain; CUE – a ubiquitin-binding domain.
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For some details see [[TIR1 ubiquitin ligase]].
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== 3D Structures of ubiquitin protein ligase==
== 3D Structures of ubiquitin protein ligase==
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[[Ubiquitin protein ligase 3D structures]]
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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===UPL Cbl===
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[[2y1m]] – hUPL - human<br />
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[[1d5f]] – hUPL catalytic domain <br />
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[[2dk3]] – hUPL catalytic domain - NMR<br />
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[[1yiu]] – hUPL WW3 domain - NMR<br />
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[[2oo9]], [[2ooa]], [[2oob]] – hUPL UBA domain <br />
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[[2do6]], [[2ekk]], [[2jnh]], [[2juj]] – hUPL UBA domain - NMR<br />
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[[3vgo]] – hUPL N terminal <br />
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[[2kr1]] – hUPL N terminal - NMR <br />
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[[2ldr]] – hUPL helix-ring domain - NMR <br />
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[[2d9s]] – mUPL UBA domain – mouse - NMR<br />
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''UPL Cbl complex''
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[[1yvh]] – hUPL TKB domain + APS adaptor protein<br />
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[[3bum]], [[3bun]], [[3buo]], [[3buw]], [[3bux]], [[3ob1]], [[3ob2]], [[3rlf]], [[3pfv]] – hUPL TKB domain + peptide <br />
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[[2y1n]] – hUPL residues 47-435 + ZAP peptide <br />
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[[4a4b]], [[4a4c]] – hUPL TKB domain (mutant) + ZAP peptide + ubiquitin conjugating enzyme E2 <br />
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[[1c4z]] – hUPL catalytic domain + ubiquitin conjugating enzyme E2 <br />
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[[4a49]] – hUPL residues 354-435 + ubiquitin conjugating enzyme E2 <br />
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===UPL SIAH1===
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[[2a25]] – hUPL substrate binding domain + calcyclin-binding protein peptide <br />
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[[2an6]] – mUPL residues 92-282 + phyllopod peptide <br />
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===UPL NEDD4===
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[[1wr3]], [[1wr4]], [[1wr7]] – mUPL WW domain - NMR <br />
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[[2oni]] – hUPL catalytic domain <br />
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[[3b7y]] – hUPL C2 domain <br />
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''UPL NEDD4 complex''
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[[1i5h]] – rUPL WW3 domain + amiloride-sensitive Na channel β subunit – rat <br />
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[[2ltx]], [[2lty]] – hUPL WW2 domain + peptide - NMR <br />
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[[2ez5]] – UPL WW3 domain + COMM LPSY peptide – Drosophila melanogaster - NMR <br />
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[[2kpz]], [[2kq0]], [[2laj]], [[2ltz]] – hUPL WW3 domain + peptide - NMR <br />
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[[2lb2]] – hUPL 2nd domain + peptide - NMR <br />
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[[3m7f]] – hUPL C2 domain + growth factor receptor bound protein<br />
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[[3jvz]], [[3jw0]] – hUPL HECT domain + ubiquitin + ubiquitin-conjugating enzyme<br />
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[[2xbb]] – hUPL HECT domain + ubiquitin <br />
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===UPL CNOT4===
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[[2cpi]] – mUPL RNA recognition motif - NMR <br />
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===UPL RING2===
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[[2ckl]] – mUPL RING domain + polycomb group ring finger protein 4 <br />
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[[2h0d]] – mUPL RING domain + B lymphoma MO-MLV insertion region <br />
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[[3h8h]] – hUPL C terminal <br />
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[[3gs2]] – hUPL C terminal + chromobox protein homolog<br />
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[[3ixs]] – hUPL C terminal (mutant) + RING1 and YY1-binding protein<br />
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===UPL RNF===
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[[2csw]] – hUPL FHA domain - NMR <br />
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[[3icu]] – hUPL protease-associated domain <br />
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[[3l11]], [[4ayc]] – hUPL RING domain <br />
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[[3v3l]] – hUPL WWE domain <br />
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[[2rsf]] – mUPL WWE domain + ATP<br />
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[[4epo]] – hUPL residues 345-485 + ubiquitin conjugating enzyme E2 <br />
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[[4ap4]] – hUPL residues 131-195 + ubiquitin conjugating enzyme E2 + ubiquitin<br />
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===UPL PRKIN===
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[[2jmo]] – hUPL IBR domain - NMR <br />
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[[2pie]] – hUPL FHA domain <br />
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[[2zeq]] – hUPL ubiquitin-like domain <br />
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[[3b1l]] – mUPL ubiquitin-like domain <br />
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[[2knb]] – rUPL + endophilin - NMR <br />
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===UPL ITCHY===
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[[2jo9]] – mUPL WW3 domain + Epstein-Barr virus peptide - NMR <br />
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[[2joc]], [[2ysf]], [[2kyk]] – mUPL WW domain - NMR <br />
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[[3tug]] – hUPL HECT domain <br />
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===UPL UHRF===
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[[3sox]], [[3zvz]] – hUPL PHD finger <br />
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[[2e6s]], [[2lgl]] – hUPL PHD finger - NMR <br />
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[[3bi7]], [[2pb7]], [[2zkg]], [[3dwh]], [[3oln]] – hUPL SRA domain <br />
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[[3db4]] – hUPL TUDOR domain <br />
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[[3fl2]] – hUPL RING domain <br />
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''UPL UHRF complex''
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[[3clz]], [[2zkd]], [[2zke]], [[2zkf]] – hUPL SRA domain + DNA<br />
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[[2zo0]], [[2zo1]], [[2zo2]], [[3f8i]], [[3f8j]], [[3fde]] – mUPL SRA domain + DNA<br />
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[[3sou]], [[3sow]], [[3shb]], [[2lgg]], [[3t6r]], [[zvy]], [[3ask]], [[3asl]], [[4gy5]] – hUPL PHD finger + histone H3 peptide<br />
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[[2lgk]] – hUPL PHD finger + histone H3 peptide - NMR<br />
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[[3db3]] – hUPL TUDOR domain + histone H3 peptide<br />
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[2l3r]] – hUPL TUDOR domain + histone H3 peptide - NMR<br />
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===UPL SMURF===
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[[2jqz]] – hUPL - NMR <br />
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[[2kxq]] – hUPL WW2 and WW3 + peptide<br />
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[[2laz]], [[2lb0]], [[2lb1]], [[2ltx]] – hUPL WW + peptide - NMR<br />
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[[3pyc]] – hUPL C2 domain <br />
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===UPL EDD1===
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[[2qho]] – hUPL UBA domain + ubiquitin <br />
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===UPL LNX===
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[[3b76]] – hUPL 3rd PDZ domain <br />
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===UPL WWP1===
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[[2jqz]] – hUPL WW4 domain - NMR <br />
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===UPL HECTD1===
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[[3dkm]] – hUPL CPH domain <br />
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[2lc3]] – hUPL helical bundle domain - NMR<br />
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===UPL TRIM===
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[[3ddt]] – hUPL B2-box <br />
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[[3lrq]] – hUPL N terminal <br />
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[[3u5m]] – hUPL PHD+Bromo domains <br />
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[[3u5n]], [[3u5o]], [[3u5p]] – hUPL PHD+Bromo domain + H3-histone peptide <br />
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===UPL HUWE1===
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[[3g1n]] – hUPL catalytic domain <br />
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[[3h1d]] – hUPL HECT domain (mutant)<br />
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===UPL MYCBP2===
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[[3gbw]] – mUPL 1st PHR domain <br />
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[[3hwj]] – mUPL 2nd PHR domain <br />
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===UPL HECW===
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[[3l4h]] – hUPL WW2 and helical box domains <br />
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[[2lfe]] – hUPL N terminal - NMR<br />
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===UPL Arkadia===
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[[2kiz]] – hUPL RING-H2 finger domain - NMR<br />
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===UPL UBR===
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[[3ny1]], [[3ny2]] – hUPL UBR-box <br />
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[[3pt3]] – hUPL C terminal <br />
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[[3ny3]] – hUPL UBR-box + N-degron<br />
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[[3nih]], [[3nii]], [[3nij]], [[3nik]], [[3nil]], [[3nim]], [[3nin]] – yUPL UBR-box + peptide - yeast<br />
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[[3nis]], [[3nit]] – yUPL UBR-box <br />
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[[3ntw]] – rUPL MLLE domain + peptide <br />
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===UPL Praja===
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[[2l0b]] – hUPL RING-type zinc finger domain - NMR<br />
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===UPL CHFR===
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[[2xoc]], [[2xoy]], [[2xoz]] – hUPL C terminal + nucleotide<br />
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[[2xp0]] – hUPL C terminal <br />
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===UPL DTX3L===
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[[3pg6]] – hUPL C terminal <br />
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===UPL RSP5===
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[[3olm]] – hUPL HECT + WW3 domains + ubiquitin <br />
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===UPL MYLIP===
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[[2yhn]] – hUPL RING domain <br />
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[[2yho]] – hUPL RING domain + ubiquitin-conjugating enzyme<br />
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===UPL RBX===
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[[2lgv]] – hUPL residues 5-108 (mutant) - NMR <br />
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[[3rtr]], [[4f52]] – hUPL residues 5-108 + cullin-1 <br />
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[[4a0k]] – hUPL residues 12-108 + cullin-4B + cullin-associated NEDD8-dissociated protein<br />
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[[4a0l]] – hUPL residues 12-108 + cullin-4B + DNA damage-binding protein + DNA<br />
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===UPL FANCL===
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[[3zqs]] – hUPL residues 109-294<br />
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===UPL SOPA===
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[[3sy2]] – UPL residues 165-782 + ubiquitin + ubiquitin-conjugating enzyme – ''Salmonella enterica''<br />
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===UPL HAKAI===
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[[3vk6]] – mUPL phosphotyrosine-binding domain<br />
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===UPL AMFR===
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[[4g3o]] – hUPL CUE domain<br />
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[[2lvn]] – hUPL CUE domain - NMR<br />
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[[2lvo]], [[2lvp]], [[2lvq]] – hUPL CUE domain + ubiquitin - NMR<br />
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===UPL XIAP===
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[[4ic2]] – hUPL RING domain<br />
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[[4ic3]] – hUPL RING domain (mutant)<br />
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[[4hy0]] – hUPL residues 238-357<br />
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===UPL MDM2===
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</StructureSection>
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[[MDM2]]
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==References==
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<references />
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[[Category:Topic Page]] + phosphoubiquitin

Current revision

Human UPL HOIP (magenta) complex with ubiquitin (green), imidazole and Zn+2 ion (grey) 4ljo

Drag the structure with the mouse to rotate

References

  1. ↑ Ardley HC, Robinson PA. E3 ubiquitin ligases. Essays Biochem. 2005;41:15-30. PMID:16250895 doi:http://dx.doi.org/10.1042/EB0410015
  2. ↑ Sakemi R, Yano H, Ogasawara S, Akiba J, Nakashima O, Fukahori S, Sata M, Kojiro M. X-linked inhibitor of apoptosis (XIAP) and XIAP-associated factor-1 expressions and their relationship to apoptosis in human hepatocellular carcinoma and non-cancerous liver tissues. Oncol Rep. 2007 Jul;18(1):65-70. PMID:17549347
  3. ↑ Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 2014 Jan;1843(1):47-60. PMID:23747565 doi:10.1016/j.bbamcr.2013.05.026
  4. ↑ Petrova T, Zhang J, Nanda SK, Figueras-Vadillo C, Cohen P. HOIL-1-catalysed, ester-linked ubiquitylation restricts IL-18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages. FEBS J. 2021 Oct;288(20):5909-5924. PMID:33932090 doi:10.1111/febs.15896
  5. ↑ Aguilar C, Lenoir C, Lambert N, Begue B, Brousse N, Canioni D, Berrebi D, Roy M, Gerart S, Chapel H, Schwerd T, Siproudhis L, Schappi M, Al-Ahmari A, Mori M, Yamaide A, Galicier L, Neven B, Routes J, Uhlig HH, Koletzko S, Patel S, Kanegane H, Picard C, Fischer A, Bensussan NC, Ruemmele F, Hugot JP, Latour S. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol. 2014 Nov;134(5):1131-41.e9. doi:, 10.1016/j.jaci.2014.04.031. Epub 2014 Jun 15. PMID:24942515 doi:http://dx.doi.org/10.1016/j.jaci.2014.04.031
  6. ↑ Ardley HC, Robinson PA. The role of ubiquitin-protein ligases in neurodegenerative disease. Neurodegener Dis. 2004;1(2-3):71-87. PMID:16908979 doi:http://dx.doi.org/10.1159/000080048
  7. ↑ Xu G, Jiang X, Jaffrey SR. A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition. J Biol Chem. 2013 Oct 11;288(41):29573-85. doi: 10.1074/jbc.M113.472092. Epub, 2013 Aug 27. PMID:23983124 doi:http://dx.doi.org/10.1074/jbc.M113.472092
  8. ↑ Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014 Jan 17;343(6168):305-9. doi: 10.1126/science.1244917. Epub 2013 Nov, 29. PMID:24292623 doi:http://dx.doi.org/10.1126/science.1244917
  9. ↑ Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V, Christodoulou E, Howell S, Brown NR, Dikic I, Rittinger K. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature. 2013 Oct 20. doi: 10.1038/nature12638. PMID:24141947 doi:http://dx.doi.org/10.1038/nature12638
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