Hundsrucker C, Klussmann E
Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, Berlin, Germany.
Handb Exp Pharmacol. 2008(186):483-503. doi: 10.1007/978-3-540-72843-6_20.
A-kinase-anchoring proteins (AKAPs) are a diverse family of about 50 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins such as further protein kinases, protein phosphatases and phosphodiesterases by direct protein-protein interactions to cellular compartments. Thus, AKAPs form the basis of signalling modules that integrate cellular signalling processes and limit these to defined sites. Disruption of AKAP functions by gene targeting, knockdown approaches and, in particular, pharmacological disruption of defined AKAP-dependent protein-protein interactions has revealed key roles of AKAPs in numerous processes, including the regulation of cardiac myocyte contractility and vasopressin-mediated water reabsorption in the kidney. Dysregulation of such processes causes diseases, including cardiovascular and renal disorders. In this review, we discuss AKAP functions elucidated by gene targeting and knockdown approaches, but mainly focus on studies utilizing peptides for disruption of direct AKAP-mediated protein-protein interactions. The latter studies point to direct AKAP-mediated protein-protein interactions as targets for novel drugs.
A激酶锚定蛋白（AKAPs）是一个由约50种支架蛋白组成的多样化家族。它们的定义是存在结构保守的蛋白激酶A（PKA）结合结构域。AKAPs通过直接的蛋白质-蛋白质相互作用将PKA和其他信号蛋白（如其他蛋白激酶、蛋白磷酸酶和磷酸二酯酶）束缚到细胞区室。因此，AKAPs构成了信号模块的基础，这些信号模块整合细胞信号转导过程并将其限制在特定部位。通过基因靶向、敲低方法，特别是对特定AKAP依赖性蛋白质-蛋白质相互作用的药理学破坏来破坏AKAP功能，揭示了AKAPs在许多过程中的关键作用，包括心肌细胞收缩力的调节和肾脏中血管加压素介导的水重吸收。这些过程的失调会导致疾病，包括心血管和肾脏疾病。在本综述中，我们讨论了通过基因靶向和敲低方法阐明的AKAP功能，但主要关注利用肽破坏直接的AKAP介导的蛋白质-蛋白质相互作用的研究。后者的研究指出直接的AKAP介导的蛋白质-蛋白质相互作用作为新型药物的靶点。
