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==Gumby/Fam105B in complex with ubiquitin==
==Gumby/Fam105B in complex with ubiquitin==
<StructureSection load='4ksk' size='340' side='right' caption='[[4ksk]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='4ksk' size='340' side='right'caption='[[4ksk]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ksk]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KSK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KSK FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ksk]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KSK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KSK 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='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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ksj|4ksj]], [[4ksl|4ksl]]</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=4ksk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ksk OCA], [https://pdbe.org/4ksk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ksk RCSB], [https://www.ebi.ac.uk/pdbsum/4ksk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ksk ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FAM105B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), UBC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4ksk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ksk OCA], [http://pdbe.org/4ksk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ksk RCSB], [http://www.ebi.ac.uk/pdbsum/4ksk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ksk ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/UBC_HUMAN UBC_HUMAN]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref>
[https://www.uniprot.org/uniprot/OTUL_HUMAN OTUL_HUMAN] Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response. Associates with the LUBAC complex via direct interaction with RNF31 and counteracts its action by cleaving linear polyubiquitin chains to substrates. Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex. Acts as a negative regulator of NF-kappa-B by counteracting activity of the LUBAC complex. Plays a key role in innate immune response: required to restrict linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation, probably to limit NOD2-dependent proinflammatory signaling.<ref>PMID:23827681</ref> <ref>PMID:23806334</ref> <ref>PMID:23746843</ref> <ref>PMID:23708998</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==
*[[Ubiquitin|Ubiquitin]]
*[[3D structures of ubiquitin|3D structures of ubiquitin]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Ceccarelli, D F]]
[[Category: Large Structures]]
[[Category: Juang, Y C]]
[[Category: Ceccarelli DF]]
[[Category: Sicheri, F]]
[[Category: Juang Y-C]]
[[Category: Deubiquitinase]]
[[Category: Sicheri F]]
[[Category: Hydrolase]]
[[Category: Hydrolase-protein binding complex]]
[[Category: Otu domain]]
[[Category: Ubiquitin]]

Revision as of 12:11, 7 December 2022

Gumby/Fam105B in complex with ubiquitinGumby/Fam105B in complex with ubiquitin

Structural highlights

4ksk is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OTUL_HUMAN Deubiquitinase that specifically removes linear ('Met-1'-linked) polyubiquitin chains to substrates and acts as a regulator of angiogenesis and innate immune response. Associates with the LUBAC complex via direct interaction with RNF31 and counteracts its action by cleaving linear polyubiquitin chains to substrates. Required during angiogenesis, craniofacial and neuronal development by regulating the canonical Wnt signaling together with the LUBAC complex. Acts as a negative regulator of NF-kappa-B by counteracting activity of the LUBAC complex. Plays a key role in innate immune response: required to restrict linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation, probably to limit NOD2-dependent proinflammatory signaling.[1] [2] [3] [4]

Publication Abstract from PubMed

A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-kappaB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.

The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis.,Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, Huang H, Dunham WH, Fukumura R, Xie G, Gondo Y, Raught B, Gingras AC, Sicheri F, Cordes SP Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24. PMID:23708998[5]

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

See Also

References

  1. ↑ Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H, Komander D. OTU Deubiquitinases Reveal Mechanisms of Linkage Specificity and Enable Ubiquitin Chain Restriction Analysis. Cell. 2013 Jul 3;154(1):169-84. doi: 10.1016/j.cell.2013.05.046. PMID:23827681 doi:10.1016/j.cell.2013.05.046
  2. ↑ Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, Mailand N, Choudhary C, Komander D, Gyrd-Hansen M. OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013 Jun 27;50(6):818-30. doi: 10.1016/j.molcel.2013.06.004. PMID:23806334 doi:http://dx.doi.org/10.1016/j.molcel.2013.06.004
  3. ↑ Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, Wauer T, Hospenthal MK, Gyrd-Hansen M, Krappmann D, Hofmann K, Komander D. OTULIN Antagonizes LUBAC Signaling by Specifically Hydrolyzing Met1-Linked Polyubiquitin. Cell. 2013 Jun 6;153(6):1312-26. doi: 10.1016/j.cell.2013.05.014. PMID:23746843 doi:10.1016/j.cell.2013.05.014
  4. ↑ Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, Huang H, Dunham WH, Fukumura R, Xie G, Gondo Y, Raught B, Gingras AC, Sicheri F, Cordes SP. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24. PMID:23708998 doi:10.1038/nature12296
  5. ↑ Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, Huang H, Dunham WH, Fukumura R, Xie G, Gondo Y, Raught B, Gingras AC, Sicheri F, Cordes SP. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24. PMID:23708998 doi:10.1038/nature12296

4ksk, resolution 2.40Å

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