Lee E K, Diehl J A
1] Leonard and Madlyn Abramson Family Cancer Research Institute, Philadelphia, PA, USA [2] Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Oncogene. 2014 Apr 17;33(16):2011-8. doi: 10.1038/onc.2013.144. Epub 2013 Apr 29.
Substrate-specific degradation is a key feature of the ubiquitin proteasome system. Substrate specificity is typically directed by the E3 or ubiquitin ligase; such specificity can be conferred either by ligase modification or expression or conversely via modification of substrates that permit their recognition by a specific E3 ligase. The most well-known example of such complexes are the Cullin-RING ligases (CRLs). CRLs are composed of one of seven cullin-family scaffold proteins; the CRL serves as a scaffold that interacts directly with a RING-domain enzyme (Rbx1/2) through an extensive protein-protein interface within the globular C-terminal domain. At the N terminus, the cullin associates with an adaptor protein through cullin-repeat motifs. This adaptor, in turn, facilitates recruitment of a substrate-specifying factor that recruits the target to be ubiquitylated. The prototypical CRL is the cul1-containing complex, commonly referred to as the Skp1-Cul1-Fbox (SCF) ligase. SCF ligases contribute to the timely destruction of numerous substrates thereby ensuring normal cell growth. The importance of SCF function is highlighted by cancer-specific alterations in either the expression or the function of select F-box substrate-specific adaptors that results in neoplastic conversion. Herein, we discuss the current understanding of SCF function and contribution to cell biology.
底物特异性降解是泛素蛋白酶体系统的一个关键特征。底物特异性通常由E3或泛素连接酶决定；这种特异性既可以通过连接酶的修饰或表达来赋予，也可以通过底物的修饰来实现，使底物能够被特定的E3连接酶识别。此类复合物最著名的例子是Cullin-RING连接酶（CRLs）。CRLs由七种cullin家族支架蛋白之一组成；CRL作为一种支架，通过球状C末端结构域内广泛的蛋白质-蛋白质界面直接与RING结构域酶（Rbx1/2）相互作用。在N末端，cullin通过cullin重复基序与衔接蛋白结合。反过来，这种衔接蛋白有助于招募底物特异性因子，该因子招募待泛素化的靶标。典型的CRL是含cul1的复合物，通常称为Skp1-Cul1-Fbox（SCF）连接酶。SCF连接酶有助于及时降解众多底物，从而确保正常的细胞生长。特定F-box底物特异性衔接蛋白的表达或功能发生癌症特异性改变导致肿瘤转化，这突出了SCF功能的重要性。在此，我们讨论目前对SCF功能及其对细胞生物学贡献的理解。
