8enp

From Proteopedia

(Difference between revisions)

Current revision

UBE3A isoform 3 AZUL

Structural highlights

8enp is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

UBE3A_HUMAN Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:105830; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.^[1] ^[2]

Function

UBE3A_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Abnormalities in the expression of the ubiquitin ligase UBE3A (ubiquitin-protein ligase E3A)/E6AP (human papillomavirus E6-associated protein) are implicated in neurological disorders including Angelman syndrome and autism. Human UBE3A is expressed as three protein isoforms that differ in their abundance and subcellular localization. While previous studies indicate isoform-specific functions, the distinct roles of each isoform in human development remain unknown. The isoforms differ only by an extension at the N-terminal end of the AZUL (N-terminal zinc [Zn]-binding domain Amino-terminal Zn finger of the UBE3A Ligase) domain, which tethers UBE3A to the proteasome by interaction with proteasomal subunit Rpn10. Differences in the structure and biophysical properties of UBE3A isoforms likely contribute to their individual functions. Here, we use a combination of NMR spectroscopy and other biophysical and biochemical techniques to identify differences in structure, dynamics, and the Rpn10 binding of the AZUL isoforms. We show that the AZUL domain structure is retained in all three isoforms with an extended N-terminal helix in longer isoforms 2 and 3. Accordingly, all isoforms could effectively associate with the Rpn10. Significant differences between the isoforms were found in their propensities to multimerize where only the longer isoforms 2 and 3 of the AZUL domain could form dimers, which may play a role in the previously observed oligomerization-dependent activation of the UBE3A. Moreover, our NMR relaxation dispersion experiments revealed a dynamic Zn-coordination site in isoforms 1 and 3, but not in isoform 2 of UBE3A, suggesting its possible isoform-specific sensitivity to oxidative stress. This structural and biophysical characterization of the isoforms will advance our understanding of isoform-specific functions of UBE3A and may contribute to future treatment strategies for Angelman syndrome and other UBE3A-related diseases.

Differences in structure, dynamics, and zinc coordination between isoforms of human ubiquitin ligase UBE3A.,Bregnard TA, Fairchild D, Chen X, Erlandsen H, Tarasov SG, Walters KJ, Korzhnev DM, Bezsonova I J Biol Chem. 2024 Dec 30;301(2):108149. doi: 10.1016/j.jbc.2024.108149. PMID:39742997^[9]

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

References

↑ Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jager D, Jager E, Knuth A, Chen YT, Old LJ. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int J Cancer. 1999 Nov 12;83(4):456-64. PMID:10508479
↑ Malzac P, Webber H, Moncla A, Graham JM, Kukolich M, Williams C, Pagon RA, Ramsdell LA, Kishino T, Wagstaff J. Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet. 1998 Jun;62(6):1353-60. PMID:9585605 doi:S0002-9297(07)62776-1
↑ Kumar S, Talis AL, Howley PM. Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem. 1999 Jun 25;274(26):18785-92. PMID:10373495
↑ Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y. E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ. 2009 Aug;16(8):1156-66. Epub 2009 Mar 27. PMID:19325566 doi:cdd200931
↑ Mishra A, Godavarthi SK, Maheshwari M, Goswami A, Jana NR. The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. J Biol Chem. 2009 Apr 17;284(16):10537-45. Epub 2009 Feb 20. PMID:19233847 doi:M806804200
↑ Shimoji T, Murakami K, Sugiyama Y, Matsuda M, Inubushi S, Nasu J, Shirakura M, Suzuki T, Wakita T, Kishino T, Hotta H, Miyamura T, Shoji I. Identification of annexin A1 as a novel substrate for E6AP-mediated ubiquitylation. J Cell Biochem. 2009 Apr 15;106(6):1123-35. PMID:19204938 doi:10.1002/jcb.22096
↑ Mishra A, Godavarthi SK, Jana NR. UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis. 2009 Oct;36(1):26-34. Epub 2009 Jul 8. PMID:19591933 doi:S0969-9961(09)00159-4
↑ Martinez-Noel G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, Howley PM. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol. 2012 Aug;32(15):3095-106. doi: 10.1128/MCB.00201-12. Epub 2012 May, 29. PMID:22645313 doi:10.1128/MCB.00201-12
↑ Bregnard TA, Fairchild D, Chen X, Erlandsen H, Tarasov SG, Walters KJ, Korzhnev DM, Bezsonova I. Differences in structure, dynamics, and zinc coordination between isoforms of human ubiquitin ligase UBE3A. J Biol Chem. 2024 Dec 30;301(2):108149. PMID:39742997 doi:10.1016/j.jbc.2024.108149

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/8enp"

Categories: Homo sapiens | Large Structures | Bezsonova I | Bregnard TA

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8enp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8ENP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ENP FirstGlance]. <br>
-</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
 <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=8enp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8enp OCA], [https://pdbe.org/8enp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8enp RCSB], [https://www.ebi.ac.uk/pdbsum/8enp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8enp ProSAT]</span></td></tr>
@@ Line 12: / Line 12: @@
 == Function ==
 [https://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.<ref>PMID:10373495</ref> <ref>PMID:19325566</ref> <ref>PMID:19233847</ref> <ref>PMID:19204938</ref> <ref>PMID:19591933</ref> <ref>PMID:22645313</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Abnormalities in the expression of the ubiquitin ligase UBE3A (ubiquitin-protein ligase E3A)/E6AP (human papillomavirus E6-associated protein) are implicated in neurological disorders including Angelman syndrome and autism. Human UBE3A is expressed as three protein isoforms that differ in their abundance and subcellular localization. While previous studies indicate isoform-specific functions, the distinct roles of each isoform in human development remain unknown. The isoforms differ only by an extension at the N-terminal end of the AZUL (N-terminal zinc [Zn]-binding domain Amino-terminal Zn finger of the UBE3A Ligase) domain, which tethers UBE3A to the proteasome by interaction with proteasomal subunit Rpn10. Differences in the structure and biophysical properties of UBE3A isoforms likely contribute to their individual functions. Here, we use a combination of NMR spectroscopy and other biophysical and biochemical techniques to identify differences in structure, dynamics, and the Rpn10 binding of the AZUL isoforms. We show that the AZUL domain structure is retained in all three isoforms with an extended N-terminal helix in longer isoforms 2 and 3. Accordingly, all isoforms could effectively associate with the Rpn10. Significant differences between the isoforms were found in their propensities to multimerize where only the longer isoforms 2 and 3 of the AZUL domain could form dimers, which may play a role in the previously observed oligomerization-dependent activation of the UBE3A. Moreover, our NMR relaxation dispersion experiments revealed a dynamic Zn-coordination site in isoforms 1 and 3, but not in isoform 2 of UBE3A, suggesting its possible isoform-specific sensitivity to oxidative stress. This structural and biophysical characterization of the isoforms will advance our understanding of isoform-specific functions of UBE3A and may contribute to future treatment strategies for Angelman syndrome and other UBE3A-related diseases.
+Differences in structure, dynamics, and zinc coordination between isoforms of human ubiquitin ligase UBE3A.,Bregnard TA, Fairchild D, Chen X, Erlandsen H, Tarasov SG, Walters KJ, Korzhnev DM, Bezsonova I J Biol Chem. 2024 Dec 30;301(2):108149. doi: 10.1016/j.jbc.2024.108149. PMID:39742997<ref>PMID:39742997</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 8enp" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
 == References ==
 <references/>

8enp

From Proteopedia

Current revision

UBE3A isoform 3 AZUL

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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