7T1Z
Structure of the Fbw7-Skp1-MycNdegron complex
Summary for 7T1Z
| Entry DOI | 10.2210/pdb7t1z/pdb |
| Related | 7T1Y |
| Descriptor | S-phase kinase-associated protein 1, F-box/WD repeat-containing protein 7, Myc proto-oncogene N terminal degron, ... (5 entities in total) |
| Functional Keywords | ubiquitin ligase, wd40, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 71410.66 |
| Authors | Wang, B.,Rusnac, D.V.,Clurman, B.E.,Zheng, N. (deposition date: 2021-12-02, release date: 2022-02-16, Last modification date: 2024-10-23) |
| Primary citation | Welcker, M.,Wang, B.,Rusnac, D.V.,Hussaini, Y.,Swanger, J.,Zheng, N.,Clurman, B.E. Two diphosphorylated degrons control c-Myc degradation by the Fbw7 tumor suppressor. Sci Adv, 8:eabl7872-eabl7872, 2022 Cited by PubMed Abstract: c-Myc (hereafter, Myc) is a cancer driver whose abundance is regulated by the SCF 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. PubMed: 35089787DOI: 10.1126/sciadv.abl7872 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.77 Å) |
Structure validation
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