Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
Graduate Interdisciplinary Program in Neuroscience, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
ACS Chem Neurosci. 2020 Sep 2;11(17):2492-2505. doi: 10.1021/acschemneuro.0c00307. Epub 2020 Aug 4.
Collapsin response mediator proteins (CRMPs) are ubiquitously expressed phosphoproteins that coordinate cytoskeletal formation and regulate cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. Accumulating evidence has also demonstrated a key role for CRMP2 in trafficking of voltage- and ligand-gated ion channels. These functions are tightly regulated by post-translational modifications including phosphorylation and SUMOylation (addition of a small ubiquitin like modifier). Over the past decade, it has become increasingly clear that dysregulated post-translational modifications of CRMP2 contribute to the pathomechanisms of diverse diseases, including cancer, neurodegenerative diseases, chronic pain, and bipolar disorder. Here, we review the discovery, functions, and current putative preclinical and clinical therapeutics targeting CRMP2. These potential therapeutics include CRMP2-based peptides that inhibit protein-protein interactions and small-molecule compounds. Capitalizing on the availability of structural information, we identify druggable pockets on CRMP2 and predict binding modes for five known CRMP2-targeting compounds, setting the stage for optimization and de novo drug discovery targeting this multifunctional protein.
collapsin 反应介质蛋白（CRMPs）是广泛表达的磷酸化蛋白，它们协调细胞骨架的形成并调节细胞分裂、迁移、极性和突触连接。在五个家族成员中，研究最多的 CRMP2 最著名的是其与微管蛋白异二聚体的亲和力及其在调节微管网络中的功能。越来越多的证据表明，CRMP2 在电压门控和配体门控离子通道的运输中也起着关键作用。这些功能受到翻译后修饰（包括磷酸化和 SUMOylation（添加小泛素样修饰物））的严格调节。在过去的十年中，越来越清楚的是，CRMP2 的失调翻译后修饰导致了包括癌症、神经退行性疾病、慢性疼痛和双相情感障碍在内的多种疾病的发病机制。在这里，我们回顾了 CRMP2 的发现、功能以及目前针对该蛋白的潜在临床前和临床治疗方法。这些潜在的治疗方法包括抑制蛋白-蛋白相互作用的基于 CRMP2 的肽和小分子化合物。利用结构信息的可用性，我们确定了 CRMP2 上的可药物结合口袋，并预测了五种已知的 CRMP2 靶向化合物的结合模式，为针对这种多功能蛋白的优化和从头药物发现奠定了基础。
