Structural highlights
Function
SKP1_HUMAN Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005 Oct 7;20(1):9-19. PMID:16209941 doi:10.1016/j.molcel.2005.09.003
- ↑ Li Y, Hao B. Structural basis of dimerization-dependent ubiquitination by the SCF(Fbx4) ubiquitin ligase. J Biol Chem. 2010 Apr 30;285(18):13896-906. Epub 2010 Feb 24. PMID:20181953 doi:10.1074/jbc.M110.111518
- ↑ 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
