7yv4

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human UCHL3 in complex with Farrerol

Structural highlights

7yv4 is a 1 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 1.58Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UCHL3_HUMAN Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3", and exhibits a preference towards 'Lys-48'-linked Ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurogenerative disorders.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly targets to regulate HR repair and the underlying molecular mechanisms have not been determined. Here, we find that the deubiquitinase UCHL3 is the direct target of farrerol. Mechanistically, farrerol enhanced the deubiquitinase activity of UCHL3 to promote RAD51 deubiquitination, thereby improving HR repair. Importantly, we find that embryos of somatic cell nuclear transfer (SCNT) exhibited defective HR repair, increased genomic instability and aneuploidy, and that the farrerol treatment post nuclear transfer enhances HR repair, restores transcriptional and epigenetic network, and promotes SCNT embryo development. Ablating UCHL3 significantly attenuates farrerol-mediated stimulation in HR and SCNT embryo development. In summary, we identify farrerol as an activator of the deubiquitinase UCHL3, highlighted the importance of HR and epigenetic changes in SCNT reprogramming and provide a feasible method to promote SCNT efficiency.

Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer.,Zhang W, Wang M, Song Z, Fu Q, Chen J, Zhang W, Gao S, Sun X, Yang G, Zhang Q, Yang J, Tang H, Wang H, Kou X, Wang H, Mao Z, Xu X, Gao S, Jiang Y Nat Commun. 2023 Apr 3;14(1):1838. doi: 10.1038/s41467-023-37576-9. PMID:37012254^[6]

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

References

↑ Wilkinson KD, Lee KM, Deshpande S, Duerksen-Hughes P, Boss JM, Pohl J. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science. 1989 Nov 3;246(4930):670-3. PMID:2530630
↑ Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T. Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochem Biophys Res Commun. 1998 Oct 29;251(3):688-92. PMID:9790970 doi:S0006-291X(98)99532-8
↑ Setsuie R, Sakurai M, Sakaguchi Y, Wada K. Ubiquitin dimers control the hydrolase activity of UCH-L3. Neurochem Int. 2009 May-Jun;54(5-6):314-21. doi: 10.1016/j.neuint.2008.12.013., Epub 2008 Dec 25. PMID:19154770 doi:http://dx.doi.org/10.1016/j.neuint.2008.12.013
↑ Dennissen FJ, Kholod N, Hermes DJ, Kemmerling N, Steinbusch HW, Dantuma NP, van Leeuwen FW. Mutant ubiquitin (UBB+1) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3). FEBS Lett. 2011 Aug 19;585(16):2568-74. doi: 10.1016/j.febslet.2011.06.037. Epub , 2011 Jul 6. PMID:21762696 doi:http://dx.doi.org/10.1016/j.febslet.2011.06.037
↑ Iphofer A, Kummer A, Nimtz M, Ritter A, Arnold T, Frank R, van den Heuvel J, Kessler BM, Jansch L, Franke R. Profiling ubiquitin linkage specificities of deubiquitinating enzymes with branched ubiquitin isopeptide probes. Chembiochem. 2012 Jul 9;13(10):1416-20. doi: 10.1002/cbic.201200261. Epub 2012, Jun 11. PMID:22689415 doi:10.1002/cbic.201200261
↑ Zhang W, Wang M, Song Z, Fu Q, Chen J, Zhang W, Gao S, Sun X, Yang G, Zhang Q, Yang J, Tang H, Wang H, Kou X, Wang H, Mao Z, Xu X, Gao S, Jiang Y. Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer. Nat Commun. 2023 Apr 3;14(1):1838. PMID:37012254 doi:10.1038/s41467-023-37576-9

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7yv4"

Categories: Homo sapiens | Large Structures | Mao ZY | Xu XJ | Zhang WT

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7yv4 is ON HOLD  until Paper Publication
+==Crystal structure of human UCHL3 in complex with Farrerol==
+<StructureSection load='7yv4' size='340' side='right'caption='[[7yv4]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7yv4]] is a 1 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=7YV4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YV4 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.58&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JXY:(2~{S})-2-(4-hydroxyphenyl)-6,8-dimethyl-5,7-bis(oxidanyl)-2,3-dihydrochromen-4-one'>JXY</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=7yv4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yv4 OCA], [https://pdbe.org/7yv4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yv4 RCSB], [https://www.ebi.ac.uk/pdbsum/7yv4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yv4 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/UCHL3_HUMAN UCHL3_HUMAN] Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3", and exhibits a preference towards 'Lys-48'-linked Ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurogenerative disorders.<ref>PMID:2530630</ref> <ref>PMID:9790970</ref> <ref>PMID:19154770</ref> <ref>PMID:21762696</ref> <ref>PMID:22689415</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly targets to regulate HR repair and the underlying molecular mechanisms have not been determined. Here, we find that the deubiquitinase UCHL3 is the direct target of farrerol. Mechanistically, farrerol enhanced the deubiquitinase activity of UCHL3 to promote RAD51 deubiquitination, thereby improving HR repair. Importantly, we find that embryos of somatic cell nuclear transfer (SCNT) exhibited defective HR repair, increased genomic instability and aneuploidy, and that the farrerol treatment post nuclear transfer enhances HR repair, restores transcriptional and epigenetic network, and promotes SCNT embryo development. Ablating UCHL3 significantly attenuates farrerol-mediated stimulation in HR and SCNT embryo development. In summary, we identify farrerol as an activator of the deubiquitinase UCHL3, highlighted the importance of HR and epigenetic changes in SCNT reprogramming and provide a feasible method to promote SCNT efficiency.
-Authors:
+Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer.,Zhang W, Wang M, Song Z, Fu Q, Chen J, Zhang W, Gao S, Sun X, Yang G, Zhang Q, Yang J, Tang H, Wang H, Kou X, Wang H, Mao Z, Xu X, Gao S, Jiang Y Nat Commun. 2023 Apr 3;14(1):1838. doi: 10.1038/s41467-023-37576-9. PMID:37012254<ref>PMID:37012254</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7yv4" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mao ZY]]
+[[Category: Xu XJ]]
+[[Category: Zhang WT]]

7yv4

From Proteopedia

Current revision

Crystal structure of human UCHL3 in complex with Farrerol

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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