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6fyh

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Revision as of 09:50, 18 July 2018

Disulfide between ubiquitin G76C and the E3 HECT ligase Huwe1

Structural highlights

6fyh is a 2 chain structure with sequence from Daphnia magna and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	HUWE1, KIAA0312, KIAA1578, UREB1, HSPC272 (HUMAN)
Activity:	Transferase, with EC number 2.3.2.26
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[HUWE1_HUMAN] Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST) [MIM: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: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.^[1]

Function

[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.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

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^[9]

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

References

↑ Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Van Esch H, Chelly J, Sanlaville D, van Bokhoven H, Ropers HH, Laumonnier F, Ranieri E, Schwartz CE, Abidi F, Tarpey PS, Futreal PA, Whibley A, Raymond FL, Stratton MR, Fryns JP, Scott R, Peippo M, Sipponen M, Partington M, Mowat D, Field M, Hackett A, Marynen P, Turner G, Gecz J. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet. 2008 Feb;82(2):432-43. Epub 2008 Jan 24. PMID:18252223 doi:S0002-9297(07)00036-5
↑ Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005 Jul 1;121(7):1071-83. PMID:15989956 doi:S0092-8674(05)00356-9
↑ Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005 Jul 1;121(7):1085-95. PMID:15989957 doi:S0092-8674(05)00556-8
↑ Liu Z, Oughtred R, Wing SS. Characterization of E3Histone, a novel testis ubiquitin protein ligase which ubiquitinates histones. Mol Cell Biol. 2005 Apr;25(7):2819-31. PMID:15767685 doi:25/7/2819
↑ Yoon SY, Lee Y, Kim JH, Chung AS, Joo JH, Kim CN, Kim NS, Choe IS, Kim JW. Over-expression of human UREB1 in colorectal cancer: HECT domain of human UREB1 inhibits the activity of tumor suppressor p53 protein. Biochem Biophys Res Commun. 2005 Jan 7;326(1):7-17. PMID:15567145 doi:10.1016/j.bbrc.2004.11.004
↑ Hall JR, Kow E, Nevis KR, Lu CK, Luce KS, Zhong Q, Cook JG. Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Mol Biol Cell. 2007 Sep;18(9):3340-50. Epub 2007 Jun 13. PMID:17567951 doi:E07-02-0173
↑ Zhao X, Heng JI, Guardavaccaro D, Jiang R, Pagano M, Guillemot F, Iavarone A, Lasorella A. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. 2008 Jun;10(6):643-53. Epub 2008 May 18. PMID:18488021 doi:ncb1727
↑ Parsons JL, Tait PS, Finch D, Dianova II, Edelmann MJ, Khoronenkova SV, Kessler BM, Sharma RA, McKenna WG, Dianov GL. Ubiquitin ligase ARF-BP1/Mule modulates base excision repair. EMBO J. 2009 Oct 21;28(20):3207-15. doi: 10.1038/emboj.2009.243. Epub 2009 Aug, 27. PMID:19713937 doi:10.1038/emboj.2009.243
↑ 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

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6fyh"

@@ Line 3: / Line 3: @@
 <StructureSection load='6fyh' size='340' side='right' caption='[[6fyh]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6fyh]] is a 2 chain structure. 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 [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>
 </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>
+<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])</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'>[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>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Daphnia magna]]
+[[Category: Human]]
 [[Category: Transferase]]
 [[Category: Hartmann, M D]]
 [[Category: Jaeckl, M]]
+[[Category: Wiesner, S]]
 [[Category: Huwe1 hect]]
 [[Category: Ligase]]
 [[Category: Thioester]]
 [[Category: Ubiquitin transfer]]

6fyh

From Proteopedia

Revision as of 09:50, 18 July 2018

Disulfide between ubiquitin G76C and the E3 HECT ligase Huwe1

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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