Structural Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.
Nature. 2012 Feb 29;483(7387):59-63. doi: 10.1038/nature10883.
Ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers such as SUMO (also known as Smt3 in Saccharomyces cerevisiae) mediate signal transduction through post-translational modification of substrate proteins in pathways that control differentiation, apoptosis and the cell cycle, and responses to stress such as the DNA damage response. In yeast, the proliferating cell nuclear antigen PCNA (also known as Pol30) is modified by ubiquitin in response to DNA damage and by SUMO during S phase. Whereas Ub-PCNA can signal for recruitment of translesion DNA polymerases, SUMO-PCNA signals for recruitment of the anti-recombinogenic DNA helicase Srs2. It remains unclear how receptors such as Srs2 specifically recognize substrates after conjugation to Ub and Ubls. Here we show, through structural, biochemical and functional studies, that the Srs2 carboxy-terminal domain harbours tandem receptor motifs that interact independently with PCNA and SUMO and that both motifs are required to recognize SUMO-PCNA specifically. The mechanism presented is pertinent to understanding how other receptors specifically recognize Ub- and Ubl-modified substrates to facilitate signal transduction.
泛素（Ub）和泛素样（Ubl）修饰物，如 SUMO（在酿酒酵母中也称为 Smt3），通过对控制分化、凋亡和细胞周期以及应对应激（如 DNA 损伤反应）的途径中的底物蛋白进行翻译后修饰来介导信号转导。在酵母中，增殖细胞核抗原 PCNA（也称为 Pol30）在 DNA 损伤时被泛素修饰，在 S 期时被 SUMO 修饰。虽然 Ub-PCNA 可以发出信号招募跨损伤 DNA 聚合酶，但 SUMO-PCNA 发出信号招募抗重组 DNA 解旋酶 Srs2。目前尚不清楚 Srs2 等受体在与 Ub 和 Ubl 缀合后如何特异性识别底物。在这里，我们通过结构、生化和功能研究表明，Srs2 羧基末端结构域含有串联的受体基序，这些基序可以独立地与 PCNA 和 SUMO 相互作用，并且都需要识别 SUMO-PCNA 。提出的机制对于理解其他受体如何特异性识别 Ub 和 Ubl 修饰的底物以促进信号转导具有重要意义。
