7t1z
Structure of the Fbw7-Skp1-MycNdegron complex
Structural highlights
FunctionFBXW7_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 PubMedc-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
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