6fyh: Difference between revisions

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==Disulfide between ubiquitin G76C and the E3 HECT ligase Huwe1==
==Disulfide between ubiquitin G76C and the E3 HECT ligase Huwe1==
<StructureSection load='6fyh' size='340' side='right' caption='[[6fyh]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
<StructureSection load='6fyh' size='340' side='right'caption='[[6fyh]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6fyh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Daphnia_magna Daphnia magna] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FYH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FYH FirstGlance]. <br>
<table><tr><td colspan='2'>[[6fyh]] is a 2 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=6FYH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FYH 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>, <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">X-ray diffraction, [[Resolution|Resolution]] 2.906&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HUWE1, KIAA0312, KIAA1578, UREB1, HSPC272 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), UBB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=35525 Daphnia magna])</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>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.26 2.3.2.26] </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=6fyh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fyh OCA], [https://pdbe.org/6fyh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fyh RCSB], [https://www.ebi.ac.uk/pdbsum/6fyh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fyh 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=6fyh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fyh OCA], [http://pdbe.org/6fyh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fyh RCSB], [http://www.ebi.ac.uk/pdbsum/6fyh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fyh ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/HUWE1_HUMAN HUWE1_HUMAN]] Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST) [MIM:[http://omim.org/entry/300706 300706]]; also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability. Associated phenotypes include macrocephaly and variable contractures.  A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17) [MIM:[http://omim.org/entry/300705 300705]]; also known as mental retardation X-linked type 31 (MRX31). Mental retardation is characterized by significantly sub-average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation.<ref>PMID:18252223</ref> 
== Function ==
[[http://www.uniprot.org/uniprot/HUWE1_HUMAN HUWE1_HUMAN]] E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Regulates apoptosis by catalyzing the polyubiquitination and degradation of MCL1. Mediates monoubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair. Also ubiquitinates the p53/TP53 tumor suppressor and core histones including H1, H2A, H2B, H3 and H4. Binds to an upstream initiator-like sequence in the preprodynorphin gene. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN. May regulate abundance of CDC6 after DNA damage by polyubiquitinating and targeting CDC6 to degradation.<ref>PMID:15989956</ref> <ref>PMID:15989957</ref> <ref>PMID:15767685</ref> <ref>PMID:15567145</ref> <ref>PMID:17567951</ref> <ref>PMID:18488021</ref> <ref>PMID:19713937</ref>  [[http://www.uniprot.org/uniprot/UBB_HUMAN UBB_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> 
<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 protein ligase|Ubiquitin protein ligase]]
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
*[[3D structures of ubiquitin|3D structures of ubiquitin]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Daphnia magna]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Transferase]]
[[Category: Hartmann MD]]
[[Category: Hartmann, M D]]
[[Category: Jaeckl M]]
[[Category: Jaeckl, M]]
[[Category: Wiesner S]]
[[Category: Wiesner, S]]
[[Category: Huwe1 hect]]
[[Category: Ligase]]
[[Category: Thioester]]
[[Category: Ubiquitin transfer]]

Latest revision as of 10:58, 17 October 2024

Disulfide between ubiquitin G76C and the E3 HECT ligase Huwe1Disulfide between ubiquitin G76C and the E3 HECT ligase Huwe1

Structural highlights

6fyh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.906Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Ubiquitin (Ub) ligases (E3s) catalyze the attachment of Ub chains to target proteins and thereby regulate a wide array of signal transduction pathways in eukaryotes. In HECT-type E3s, Ub first forms a thioester intermediate with a strictly conserved Cys in the C-lobe of the HECT domain and is then ligated via an isopeptide bond to a Lys residue in the substrate or a preceding Ub in a poly-Ub chain. To date, many key aspects of HECT-mediated Ub transfer have remained elusive. Here, we provide structural and functional insights into the catalytic mechanism of the HECT-type ligase Huwe1 and compare it to the unrelated, K63-specific Smurf2 E3, a member of the Nedd4 family. We found that the Huwe1 HECT domain, in contrast to Nedd4-family E3s, prioritizes K6- and K48-poly-Ub chains and does not interact with Ub in a non-covalent manner. Despite these mechanistic differences, we demonstrate that the architecture of the C-lobe~Ub intermediate is conserved between Huwe1 and Smurf2 and involves a reorientation of the very C-terminal residues. Moreover, in Nedd4 E3s and Huwe1 the individual sequence composition of the Huwe1 C-terminal tail modulates ubiquitination activity, without affecting thioester formation. In sum, our data suggest that catalysis of HECT ligases hold common features, such as the beta-sheet augmentation that primes the enzymes for ligation, and variable elements, such as the sequence of the HECT C-terminal tail, that fine-tune ubiquitination activity and may aid in determining Ub chain specificity by positioning the substrate or acceptor Ub.

beta-Sheet Augmentation Is a Conserved Mechanism of Priming HECT E3 Ligases for Ubiquitin Ligation.,Jackl M, Stollmaier C, Strohaker T, Hyz K, Maspero E, Polo S, Wiesner S J Mol Biol. 2018 Jun 28. pii: S0022-2836(18)30705-8. doi:, 10.1016/j.jmb.2018.06.044. PMID:29964046[1]

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

See Also

References

  1. ↑ Jackl M, Stollmaier C, Strohaker T, Hyz K, Maspero E, Polo S, Wiesner S. beta-Sheet Augmentation Is a Conserved Mechanism of Priming HECT E3 Ligases for Ubiquitin Ligation. J Mol Biol. 2018 Jun 28. pii: S0022-2836(18)30705-8. doi:, 10.1016/j.jmb.2018.06.044. PMID:29964046 doi:http://dx.doi.org/10.1016/j.jmb.2018.06.044

6fyh, resolution 2.91Å

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