7t1z: Difference between revisions

Latest revision as of 11:32, 23 October 2024

Structure of the Fbw7-Skp1-MycNdegron complex

Structural highlights

7t1z is a 3 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 2.77Å
Ligands:	SEP, SO4, TPO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FBXW7_HUMAN Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins. Involved in the degradation of cyclin-E, MYC, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

c-Myc (hereafter, Myc) is a cancer driver whose abundance is regulated by the SCF(Fbw7) ubiquitin ligase and proteasomal degradation. Fbw7 binds to a phosphorylated Myc degron centered at threonine 58 (T58), and mutations of Fbw7 or T58 impair Myc degradation in cancers. Here, we identify a second Fbw7 phosphodegron at Myc T244 that is required for Myc ubiquitylation and acts in concert with T58 to engage Fbw7. While Ras-dependent Myc serine 62 phosphorylation (pS62) is thought to stabilize Myc by preventing Fbw7 binding, we find instead that pS62 greatly enhances Fbw7 binding and is an integral part of a high-affinity degron. Crystallographic studies revealed that both degrons bind Fbw7 in their diphosphorylated forms and that the T244 degron is recognized via a unique mode involving Fbw7 arginine 689 (R689), a mutational hotspot in cancers. These insights have important implications for Myc-associated tumorigenesis and therapeutic strategies targeting Myc stability.

Two diphosphorylated degrons control c-Myc degradation by the Fbw7 tumor suppressor.,Welcker M, Wang B, Rusnac DV, Hussaini Y, Swanger J, Zheng N, Clurman BE Sci Adv. 2022 Jan 28;8(4):eabl7872. doi: 10.1126/sciadv.abl7872. Epub 2022 Jan , 28. PMID:35089787^[6]

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

References

↑ Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature. 2001 Sep 20;413(6853):316-22. PMID:11565034 doi:https://dx.doi.org/10.1038/35095076
↑ Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol. 2001 Nov;21(21):7403-15. PMID:11585921 doi:https://dx.doi.org/10.1128/MCB.21.21.7403-7415.2001
↑ Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K, Nakayama KI. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004 May 19;23(10):2116-25. Epub 2004 Apr 22. PMID:15103331 doi:https://dx.doi.org/10.1038/sj.emboj.7600217
↑ Popov N, Herold S, Llamazares M, Schulein C, Eilers M. Fbw7 and Usp28 regulate myc protein stability in response to DNA damage. Cell Cycle. 2007 Oct 1;6(19):2327-31. Epub 2007 Jul 26. PMID:17873522
↑ Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, Moll R, Elledge SJ, Eilers M. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007 Jul;9(7):765-74. Epub 2007 Jun 10. PMID:17558397 doi:https://dx.doi.org/10.1038/ncb1601
↑ Welcker M, Wang B, Rusnac DV, Hussaini Y, Swanger J, Zheng N, Clurman BE. Two diphosphorylated degrons control c-Myc degradation by the Fbw7 tumor suppressor. Sci Adv. 2022 Jan 28;8(4):eabl7872. PMID:35089787 doi:10.1126/sciadv.abl7872

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature. 2001 Sep 20;413(6853):316-22. PMID:11565034 doi:https://dx.doi.org/10.1038/35095076

[2] Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol. 2001 Nov;21(21):7403-15. PMID:11585921 doi:https://dx.doi.org/10.1128/MCB.21.21.7403-7415.2001

[3] Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K, Nakayama KI. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004 May 19;23(10):2116-25. Epub 2004 Apr 22. PMID:15103331 doi:https://dx.doi.org/10.1038/sj.emboj.7600217

[4] Popov N, Herold S, Llamazares M, Schulein C, Eilers M. Fbw7 and Usp28 regulate myc protein stability in response to DNA damage. Cell Cycle. 2007 Oct 1;6(19):2327-31. Epub 2007 Jul 26. PMID:17873522

[5] Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, Moll R, Elledge SJ, Eilers M. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007 Jul;9(7):765-74. Epub 2007 Jun 10. PMID:17558397 doi:https://dx.doi.org/10.1038/ncb1601

[6] Welcker M, Wang B, Rusnac DV, Hussaini Y, Swanger J, Zheng N, Clurman BE. Two diphosphorylated degrons control c-Myc degradation by the Fbw7 tumor suppressor. Sci Adv. 2022 Jan 28;8(4):eabl7872. PMID:35089787 doi:10.1126/sciadv.abl7872

[1]

[2]

[3]

[4]

[5]

[6]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7t1z is ON HOLD
+==Structure of the Fbw7-Skp1-MycNdegron complex==
+<StructureSection load='7t1z' size='340' side='right'caption='[[7t1z]], [[Resolution|resolution]] 2.77&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7t1z]] is a 3 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=7T1Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T1Z 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]] 2.77&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=7t1z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t1z OCA], [https://pdbe.org/7t1z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t1z RCSB], [https://www.ebi.ac.uk/pdbsum/7t1z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t1z ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/FBXW7_HUMAN FBXW7_HUMAN] Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins. Involved in the degradation of cyclin-E, MYC, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1.<ref>PMID:11565034</ref> <ref>PMID:11585921</ref> <ref>PMID:15103331</ref> <ref>PMID:17873522</ref> <ref>PMID:17558397</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+c-Myc (hereafter, Myc) is a cancer driver whose abundance is regulated by the SCF(Fbw7) ubiquitin ligase and proteasomal degradation. Fbw7 binds to a phosphorylated Myc degron centered at threonine 58 (T58), and mutations of Fbw7 or T58 impair Myc degradation in cancers. Here, we identify a second Fbw7 phosphodegron at Myc T244 that is required for Myc ubiquitylation and acts in concert with T58 to engage Fbw7. While Ras-dependent Myc serine 62 phosphorylation (pS62) is thought to stabilize Myc by preventing Fbw7 binding, we find instead that pS62 greatly enhances Fbw7 binding and is an integral part of a high-affinity degron. Crystallographic studies revealed that both degrons bind Fbw7 in their diphosphorylated forms and that the T244 degron is recognized via a unique mode involving Fbw7 arginine 689 (R689), a mutational hotspot in cancers. These insights have important implications for Myc-associated tumorigenesis and therapeutic strategies targeting Myc stability.
-Authors: Wang, B., Rusnac, D.V., Zheng, N., Clurman, B.E.
+Two diphosphorylated degrons control c-Myc degradation by the Fbw7 tumor suppressor.,Welcker M, Wang B, Rusnac DV, Hussaini Y, Swanger J, Zheng N, Clurman BE Sci Adv. 2022 Jan 28;8(4):eabl7872. doi: 10.1126/sciadv.abl7872. Epub 2022 Jan , 28. PMID:35089787<ref>PMID:35089787</ref>
-Description: Fbw7/Skp1 in complex with Myc N terminal degron
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Rusnac, D.V]]
+<div class="pdbe-citations 7t1z" style="background-color:#fffaf0;"></div>
-[[Category: Wang, B]]
+== References ==
-[[Category: Clurman, B.E]]
+<references/>
-[[Category: Zheng, N]]
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Clurman BE]]
+[[Category: Rusnac DV]]
+[[Category: Wang B]]
+[[Category: Zheng N]]

7t1z: Difference between revisions

Latest revision as of 11:32, 23 October 2024

Structure of the Fbw7-Skp1-MycNdegron complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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