10zf: Difference between revisions

Latest revision as of 12:36, 1 July 2026

Structure of c-Cbl bound to compound 33

Structural highlights

10zf is a 1 chain structure with sequence from Homo sapiens and Schistosoma japonicum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.39Å
Ligands:	A1DCD, MG, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CBL_HUMAN Defects in CBL are the cause of Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563. A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects.^[1]

Function

GST26_SCHJA Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. GST isoenzymes appear to play a central role in the parasite detoxification system. Other functions are also suspected including a role in increasing the solubility of haematin in the parasite gut.CBL_HUMAN Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The Tyr-731 phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

References

↑ Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010 Aug 13;87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. Epub, 2010 Jul 8. PMID:20619386 doi:10.1016/j.ajhg.2010.06.015
↑ Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999 Oct 8;286(5438):309-12. PMID:10514377
↑ Howlett CJ, Robbins SM. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene. 2002 Mar 7;21(11):1707-16. PMID:11896602 doi:10.1038/sj.onc.1205228
↑ Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004 Apr 23;279(17):17660-6. Epub 2004 Jan 22. PMID:14739300 doi:10.1074/jbc.M311032200
↑ Kaabeche K, Lemonnier J, Le Mee S, Caverzasio J, Marie PJ. Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation. J Biol Chem. 2004 Aug 27;279(35):36259-67. Epub 2004 Jun 9. PMID:15190072 doi:10.1074/jbc.M402469200
↑ Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007 Jun;274(12):3078-93. Epub 2007 May 17. PMID:17509076 doi:10.1111/j.1742-4658.2007.05835.x
↑ Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ. FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival. Bone. 2008 Jun;42(6):1032-9. doi: 10.1016/j.bone.2008.02.009. Epub 2008 Feb 29. PMID:18374639 doi:10.1016/j.bone.2008.02.009
↑ Wehrle C, Van Slyke P, Dumont DJ. Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation. Biochem J. 2009 Oct 12;423(3):375-80. doi: 10.1042/BJ20091010. PMID:19689429 doi:10.1042/BJ20091010
↑ Severe N, Miraoui H, Marie PJ. The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011 Jul 8;286(27):24443-50. doi: 10.1074/jbc.M110.197525. Epub 2011, May 19. PMID:21596750 doi:10.1074/jbc.M110.197525

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010 Aug 13;87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. Epub, 2010 Jul 8. PMID:20619386 doi:10.1016/j.ajhg.2010.06.015

[2] Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999 Oct 8;286(5438):309-12. PMID:10514377

[3] Howlett CJ, Robbins SM. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene. 2002 Mar 7;21(11):1707-16. PMID:11896602 doi:10.1038/sj.onc.1205228

[4] Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004 Apr 23;279(17):17660-6. Epub 2004 Jan 22. PMID:14739300 doi:10.1074/jbc.M311032200

[5] Kaabeche K, Lemonnier J, Le Mee S, Caverzasio J, Marie PJ. Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation. J Biol Chem. 2004 Aug 27;279(35):36259-67. Epub 2004 Jun 9. PMID:15190072 doi:10.1074/jbc.M402469200

[6] Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007 Jun;274(12):3078-93. Epub 2007 May 17. PMID:17509076 doi:10.1111/j.1742-4658.2007.05835.x

[7] Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ. FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival. Bone. 2008 Jun;42(6):1032-9. doi: 10.1016/j.bone.2008.02.009. Epub 2008 Feb 29. PMID:18374639 doi:10.1016/j.bone.2008.02.009

[8] Wehrle C, Van Slyke P, Dumont DJ. Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation. Biochem J. 2009 Oct 12;423(3):375-80. doi: 10.1042/BJ20091010. PMID:19689429 doi:10.1042/BJ20091010

[9] Severe N, Miraoui H, Marie PJ. The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011 Jul 8;286(27):24443-50. doi: 10.1074/jbc.M110.197525. Epub 2011, May 19. PMID:21596750 doi:10.1074/jbc.M110.197525

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 10zf is ON HOLD  until Paper Publication
+==Structure of c-Cbl bound to compound 33==
+<StructureSection load='10zf' size='340' side='right'caption='[[10zf]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
-Authors:
+== Structural highlights ==
+<table><tr><td colspan='2'>[[10zf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Schistosoma_japonicum Schistosoma japonicum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=10ZF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=10ZF FirstGlance]. <br>
-Description:
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.39&#8491;</td></tr>
-[[Category: Unreleased Structures]]
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1DCD:2-{3-[(1r,3r)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(1-methylcyclobutyl)amino]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one'>A1DCD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <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=10zf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=10zf OCA], [https://pdbe.org/10zf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=10zf RCSB], [https://www.ebi.ac.uk/pdbsum/10zf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=10zf ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/CBL_HUMAN CBL_HUMAN] Defects in CBL are the cause of Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:[https://omim.org/entry/613563 613563]. A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects.<ref>PMID:20619386</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/GST26_SCHJA GST26_SCHJA] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.  GST isoenzymes appear to play a central role in the parasite detoxification system. Other functions are also suspected including a role in increasing the solubility of haematin in the parasite gut.[https://www.uniprot.org/uniprot/CBL_HUMAN CBL_HUMAN] Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The Tyr-731 phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function.<ref>PMID:10514377</ref> <ref>PMID:11896602</ref> <ref>PMID:14739300</ref> <ref>PMID:15190072</ref> <ref>PMID:17509076</ref> <ref>PMID:18374639</ref> <ref>PMID:19689429</ref> <ref>PMID:21596750</ref>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Schistosoma japonicum]]
+[[Category: Hsu PL]]
+[[Category: Murray J]]
+[[Category: Yu C]]

10zf: Difference between revisions

Latest revision as of 12:36, 1 July 2026

Structure of c-Cbl bound to compound 33

Structural highlights

Disease

Function

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools