7T1Y

Structure of the Fbw7-Skp1-MycCdegron complex

7T1Y の概要

• エントリーDOI: 10.2210/pdb7t1y/pdb
• 分子名称: S-phase kinase-associated protein 1, F-box/WD repeat-containing protein 7, Myc proto-oncogene protein C terminal degron, ... (5 entities in total)
• 機能のキーワード: ubiquitin ligase, wd40, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 73350.72

構造登録者

Wang, B.,Rusnac, D.V.,Clurman, B.E.,Zheng, N. (登録日: 2021-12-02, 公開日: 2022-02-16, 最終更新日: 2024-11-13)

主引用文献

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

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: 35089787
DOI: 10.1126/sciadv.abl7872

実験手法

X-RAY DIFFRACTION (2.55 Å)