Structural studies of ubiquitin-like protein modification

描述（由申请人提供）：信号转导途径依赖于可逆的化学修饰，在细胞内和细胞间传递信息。泛素和泛素样蛋白如SUMO（小泛素样修饰物）对蛋白质底物的共价修饰有助于调节细胞功能的途径，包括核转运、胞质分裂、染色体分离、G2-M细胞周期进展和转录调控等。泛素（ubiquitin，Ub）和类泛素（ubiquitin-like，Ubl）蛋白的翻译后修饰需要E1激活酶、E2结合酶和E3连接酶的顺序作用，而Ub/Ubl的加工和解结合则由Ub/Ubl特异性蛋白酶催化。泛素和SUMO结合在真核细胞核代谢和细胞周期控制中起着不可或缺的作用，我们的研究与人类健康、癌症和NIH的使命直接相关。该提案旨在通过结构、生物化学和遗传学研究来解决泛素和SUMO缀合途径组分的功能意义，这些研究将建立Ub/Ubl 1）活化，2）通过E2和E3酶的缀合，3）通过识别Ub/Ubl缀合底物的表征受体的信号转导的基础。构成泛素和SUMO蛋白缀合途径的酶、机制和因子是保守的，因此我们的研究将具有广泛的相关性，并将影响其他Ub/Ubl相关途径的研究。

DESCRIPTION (provided by applicant): Signal transduction pathways rely on reversible chemical modifications to relay information within and across cells. Covalent modification of protein substrates by ubiquitin and the ubiquitin-like proteins such as SUMO (small ubiquitin-like modifier) contribute to pathways that regulate cellular functions including nuclear transport, cytokinesis, chromosome segregation, G2-M cell cycle progression and transcriptional regulation among many others. Post-translational modification by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins requires the sequential action of E1 activating enzymes, E2 conjugating enzymes and E3 ligases while Ub/Ubl processing and deconjugation is catalyzed by Ub/Ubl-specific proteases. Ubiquitin and SUMO conjugation play an integral role in eukaryotic nuclear metabolism and cell cycle control and our studies are of direct relevance to human health, cancer, and the mission of the NIH. This proposal seeks to address the functional significance for components of the ubiquitin and SUMO conjugation pathways through structural, biochemical and genetic studies that will establish the basis for Ub/Ubl 1) activation, 2) conjugation by E2 and E3 enzymes, 3) signal transduction through characterization receptors that recognize Ub/Ubl-conjugated substrates. The enzymes, mechanisms and factors that constitute ubiquitin and SUMO protein conjugation pathways are conserved so our studies will be broadly relevant and will impact research in other Ub/Ubl-related pathways.