7mop

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of human HUWE1 in complex with DDIT4

Structural highlights

7mop 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:	Electron Microscopy, Resolution 3.3Å
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

HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors, including Mcl1, p53, DDIT4, and Myc. Although mutations in HUWE1 and related HECT ligases are widely implicated in human disease, our molecular understanding remains limited. Here we present a comprehensive investigation of full-length HUWE1, deepening our understanding of this class of enzymes. The N-terminal approximately 3,900 amino acids of HUWE1 are indispensable for proper ligase function, and our cryo-EM structures of HUWE1 offer a complete molecular picture of this large HECT ubiquitin ligase. HUWE1 forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. Structures of HUWE1 variants linked to neurodevelopmental disorders as well as of HUWE1 bound to a model substrate link the functions of this essential enzyme to its three-dimensional organization.

Solenoid architecture of HUWE1 contributes to ligase activity and substrate recognition.,Hunkeler M, Jin CY, Ma MW, Monda JK, Overwijn D, Bennett EJ, Fischer ES Mol Cell. 2021 Jul 16. pii: S1097-2765(21)00543-8. doi:, 10.1016/j.molcel.2021.06.032. PMID:34314700^[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
↑ Hunkeler M, Jin CY, Ma MW, Monda JK, Overwijn D, Bennett EJ, Fischer ES. Solenoid architecture of HUWE1 contributes to ligase activity and substrate recognition. Mol Cell. 2021 Jul 16. pii: S1097-2765(21)00543-8. doi:, 10.1016/j.molcel.2021.06.032. PMID:34314700 doi:http://dx.doi.org/10.1016/j.molcel.2021.06.032

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7mop"

Categories: Homo sapiens | Large Structures | Fischer ES | Hunkeler M

@@ Line 1: / Line 1: @@
-====
+==Cryo-EM structure of human HUWE1 in complex with DDIT4==
-<StructureSection load='7mop' size='340' side='right'caption='[[7mop]]' scene=''>
+<StructureSection load='7mop' size='340' side='right'caption='[[7mop]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7mop]] 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=7MOP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MOP FirstGlance]. <br>
-</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=7mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mop OCA], [https://pdbe.org/7mop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mop RCSB], [https://www.ebi.ac.uk/pdbsum/7mop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mop ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3&#8491;</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=7mop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mop OCA], [https://pdbe.org/7mop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mop RCSB], [https://www.ebi.ac.uk/pdbsum/7mop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mop ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/HUWE1_HUMAN HUWE1_HUMAN] Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST) [MIM:[https://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:[https://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 ==
+[https://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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors, including Mcl1, p53, DDIT4, and Myc. Although mutations in HUWE1 and related HECT ligases are widely implicated in human disease, our molecular understanding remains limited. Here we present a comprehensive investigation of full-length HUWE1, deepening our understanding of this class of enzymes. The N-terminal approximately 3,900 amino acids of HUWE1 are indispensable for proper ligase function, and our cryo-EM structures of HUWE1 offer a complete molecular picture of this large HECT ubiquitin ligase. HUWE1 forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. Structures of HUWE1 variants linked to neurodevelopmental disorders as well as of HUWE1 bound to a model substrate link the functions of this essential enzyme to its three-dimensional organization.
+Solenoid architecture of HUWE1 contributes to ligase activity and substrate recognition.,Hunkeler M, Jin CY, Ma MW, Monda JK, Overwijn D, Bennett EJ, Fischer ES Mol Cell. 2021 Jul 16. pii: S1097-2765(21)00543-8. doi:, 10.1016/j.molcel.2021.06.032. PMID:34314700<ref>PMID:34314700</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7mop" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Z-disk]]
+[[Category: Fischer ES]]
+[[Category: Hunkeler M]]

7mop

From Proteopedia

Current revision

Cryo-EM structure of human HUWE1 in complex with DDIT4

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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