Department of Biochemistry, University of Iowa, Iowa City, IA, United States.
Department of Biochemistry, University of Iowa, Iowa City, IA, United States; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States.
Int Rev Cell Mol Biol. 2019;343:129-218. doi: 10.1016/bs.ircmb.2018.05.013. Epub 2018 Jun 28.
Post-synaptic density-95, disks-large and zonula occludens-1 (PDZ) domains are small globular protein-protein interaction domains widely conserved from yeast to humans. They are composed of ∼90 amino acids and form a classical two α-helical/six β-strand structure. The prototypical ligand is the C-terminus of partner proteins; however, they also bind internal peptide sequences. Recent findings indicate that PDZ domains also bind phosphatidylinositides and cholesterol. Through their ligand interactions, PDZ domain proteins are critical for cellular trafficking and the surface retention of various ion channels. In addition, PDZ proteins are essential for neuronal signaling, memory, and learning. PDZ proteins also contribute to cytoskeletal dynamics by mediating interactions critical for maintaining cell-cell junctions, cell polarity, and cell migration. Given their important biological roles, it is not surprising that their dysfunction can lead to multiple disease states. As such, PDZ domain-containing proteins have emerged as potential targets for the development of small molecular inhibitors as therapeutic agents. Recent data suggest that the critical binding function of PDZ domains in cell signaling is more than just glue, and their binding function can be regulated by phosphorylation or allosterically by other binding partners. These studies also provide a wealth of structural and biophysical data that are beginning to reveal the physical features that endow this small modular domain with a central role in cell signaling.
突触后密度蛋白-95、大膜蛋白和闭合蛋白-1（PDZ）结构域是从小酵母到人高度保守的小球形蛋白质-蛋白质相互作用结构域。它们由约 90 个氨基酸组成，形成典型的两个α螺旋/六个β链结构。典型的配体是伴侣蛋白的 C 末端；然而，它们也结合内部肽序列。最近的研究结果表明，PDZ 结构域也与磷脂酰肌醇和胆固醇结合。通过它们的配体相互作用，PDZ 结构域蛋白对于细胞运输和各种离子通道的表面保留至关重要。此外，PDZ 蛋白对于神经元信号转导、记忆和学习也很重要。PDZ 蛋白还通过介导对于维持细胞-细胞连接、细胞极性和细胞迁移至关重要的相互作用来促进细胞骨架动力学。鉴于它们的重要生物学作用，它们的功能障碍会导致多种疾病状态也就不足为奇了。因此，PDZ 结构域蛋白已成为开发小分子抑制剂作为治疗剂的潜在靶点。最近的数据表明，PDZ 结构域在细胞信号转导中的关键结合功能不仅仅是胶，它们的结合功能可以通过磷酸化或其他结合伴侣的变构来调节。这些研究还提供了大量的结构和生物物理数据，这些数据开始揭示赋予这个小模块结构域在细胞信号转导中核心作用的物理特征。
