E3 ligases are essential scaffold proteins, facilitating the transfer of ubiquitin from E2 enzymes to lysine residues of client proteins via isopeptide bonds. The specificity of substrate binding and the expression and localization of E3 ligases can, however, endow these proteins with unique features with variable effects on mitochondrial, metabolic and CNS function. By comparing and contrasting two E3 ligases, Parkin and C-terminus of HSC70-Interacting protein (CHIP) we seek to highlight the biophysical properties that may promote mitochondrial dysfunction, acute stress signaling and critical developmental periods to cease in response to mutations in these genes. Encoded by over 600 human genes, RING-finger proteins are the largest class of E3 ligases. Parkin contains three RING finger domains, with R1 and R2 separated by an in-between region (IBR) domain. Loss-of-function mutations in Parkin were identified in patients with early onset Parkinson's disease. CHIP is a member of the Ubox family of E3 ligases. It contains an N-terminal TPR domain and forms unique asymmetric homodimers. While CHIP can substitute for mutated Parkin and enhance survival, CHIP also has unique functions. The differences between these proteins are underscored by the observation that unlike Parkin-deficient animals, CHIP-null animals age prematurely and have significantly impaired motor function. These properties make these E3 ligases appealing targets for clinical intervention. In this work, we discuss how biophysical and metabolic properties of these E3 ligases have driven rapid progress in identifying roles for E3 ligases in development, proteostasis, mitochondrial biology, and cell health, as well as new data about how these proteins alter the CNS proteome.

E3 连接酶是重要的支架蛋白，可促进泛素通过异肽键从 E2 酶转移至客户蛋白的赖氨酸残基。然而，底物结合的特异性以及 E3 连接酶的表达和定位可以赋予这些蛋白质独特的特征，对线粒体、代谢和中枢神经系统功能产生不同的影响。通过比较和对比两种 E3 连接酶、Parkin 和 HSC70 相互作用蛋白 (CHIP) 的 C 末端，我们试图强调可能促进线粒体功能障碍、急性应激信号传导和关键发育时期因这些基因突变而停止的生物物理特性。环指蛋白由 600 多个人类基因编码，是 E3 连接酶中最大的一类。Parkin 包含三个 RING 指结构域，其中 R1 和 R2 由中间区域 (IBR) 结构域分隔。在早发性帕金森病患者中发现了 Parkin 功能丧失突变。CHIP 是 E3 连接酶 Ubox 家族的成员。它包含 N 端 TPR 结构域并形成独特的不对称同二聚体。虽然CHIP可以替代突变的Parkin并增强存活率，但CHIP也具有独特的功能。与Parkin缺陷动物不同，CHIP缺失动物过早衰老并且运动功能显着受损，这一观察结果强调了这些蛋白质之间的差异。这些特性使这些 E3 连接酶成为临床干预的有吸引力的目标。在这项工作中，我们讨论了这些 E3 连接酶的生物物理和代谢特性如何推动在确定 E3 连接酶在发育、蛋白质稳态、线粒体生物学和细胞健康中的作用方面取得快速进展，以及有关这些蛋白质如何改变 CNS 蛋白质组的新数据。