Soares Dinesh C, Carlyle Becky C, Bradshaw Nicholas J, Porteous David J
ACS Chem Neurosci. 2011 Nov 16;2(11):609-632. doi: 10.1021/cn200062k. Epub 2011 Aug 5.
Disrupted in schizophrenia 1 (DISC1) is well established as a genetic risk factor across a spectrum of psychiatric disorders, a role supported by a growing body of biological studies, making the DISC1 protein interaction network an attractive therapeutic target. By contrast, there is a relative deficit of structural information to relate to the myriad biological functions of DISC1. Here, we critically appraise the available bioinformatics and biochemical analyses on DISC1 and key interacting proteins, and integrate this with the genetic and biological data. We review, analyze, and make predictions regarding the secondary structure and propensity for disordered regions within DISC1, its protein-interaction domains, subcellular localization motifs, and the structural and functional implications of common and ultrarare DISC1 variants associated with major mental illness. We discuss signaling pathways of high pharmacological potential wherein DISC1 participates, including those involving phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3). These predictions and priority areas can inform future research in the translational and potentially guide the therapeutic processes.
精神分裂症相关 1 基因（DISC1）已被确认为一系列精神疾病的遗传风险因素，越来越多的生物学研究支持这一作用，使得 DISC1 蛋白相互作用网络成为一个有吸引力的治疗靶点。相比之下，与 DISC1 众多生物学功能相关的结构信息相对匮乏。在此，我们批判性地评估了关于 DISC1 及其关键相互作用蛋白的现有生物信息学和生化分析，并将其与遗传和生物学数据整合。我们回顾、分析并预测了 DISC1 的二级结构和无序区域倾向、其蛋白相互作用结构域、亚细胞定位基序，以及与主要精神疾病相关的常见和超罕见 DISC1 变体的结构和功能影响。我们讨论了 DISC1 参与的具有高药理潜力的信号通路，包括涉及磷酸二酯酶 4（PDE4）和糖原合酶激酶 3（GSK3）的信号通路。这些预测和优先领域可为未来的转化研究提供参考，并可能指导治疗过程。
