NMR STUDIES OF SH2 DOMAINS FROM STAT PROTEINS

STAT（信号转导和转录激活因子）蛋白是 许多细胞因子信号转导途径中的关键元件 和生长因子。包括IFN-α和IFN-γ。他们提供双重服务 在这些途径中的作用，既作为信使携带 从细胞膜进入细胞核的信号， 激活特定基因的转录。放松管制， 途径可能会导致恶性状态， 增殖鉴于细胞必须同时对无数的 刺激使用这些途径的特异性， 信号至关重要。这种特异性部分是通过 STAT蛋白参与几种多蛋白复合物， 保守的SH 2结构域和磷酸酪氨酸之间的相互作用- 包含伴侣的序列使用13 C，15 N，1H三重- 共振溶液NMR方法，STAT SH 2的结构将是 以游离和肽复合形式测定，以检查 这些蛋白质-蛋白质之间特异性的分子决定因素 协会.另外。31 kDa STAT SH 2分子间结构 将产生二聚体;这种复合物在体内的形成是 对于STAT功能的转导部分尤其重要。 这些信息不仅有助于深入了解这些机制， 的分子歧视，但也促进了 合理设计药物以阻断这些相互作用。

STAT (Signal Transducers and Activators of Transcription) proteins are key elements in the signal transduction pathways of a number of cytokines and growth factors. including IFN-alpha and IFN-gamma. They serve a dual role in these pathways, functioning both as the messenger carrying the signal from the cell membrane into the nucleus and also as the message, activating the transcription of specific genes. Deregulation of these pathways could lead to malignant states arising from uncontrolled proliferation. Given that a cell must simultaneously respond to a myriad of stimuli using these pathways, specificity in transmitting these signals is vital. This specificity is achieved in part through the involvement of STAT proteins in several multiprotein complexes using interactions between a conserved SH2 domain and phosphotyrosine- containing sequences on their partners. Using 13C, 15N, 1H triple- resonance solution NMR methods, structures of the STAT SH2 will be determined in both free and peptide-complexed forms to examine the molecular determinants of specificity in these protein-protein associations. Additionally. structures of a 31kDa STAT SH2 intermolecular dimer will be generated; the formation of this complex in vivo is particularly important for the transduction part of the STAT function. This information will not only provide useful insight into the mechanisms of molecular discrimination in these systems, but also facilitate the rational design of drugs intended to block these interactions.