The 14 kDa histidine triad nucleotide-binding protein 1 (HINT1) is critical to maintain the normal function of motor neurons. Thus, a series of human HINT1 mutants cause autosomal recessive axonal neuropathy with neuromyotonia. HINT1 establishes a series of regulatory interactions with signaling proteins, some of which are enriched in motor neurons, such as the type 1 sigma receptor or intracellular domain (ICD) of transmembrane teneurin 1, both of which are also implicated in motor disturbances. In a previous study, we reported the capacity of HINT1 to remove the small ubiquitin-like modifier (SUMO) from a series of substrates and the influence of HINT1 mutants on this activity. We now report how human HINT1 mutations affect the interaction of HINT1 with the regulator of its SUMOylase activity, calcium-activated calmodulin, and its substrate SUMO. Moreover, HINT1 mutants exhibited anomalous interactions with G protein coupled receptors, such as the mu-opioid, and with glutamate N-methyl-D-aspartate receptors as well. Additionally, these HINT1 mutants showed impaired associations with transcriptional regulators such as the regulator of G protein signaling Z2 protein and the cleaved N-terminal ICD of teneurin 1. Thus, the altered enzymatic activity of human HINT1 mutants and their anomalous interactions with partner proteins may disrupt signaling pathways essential to the normal function of human motor neurons.

14 kDa 组氨酸三联体核苷酸结合蛋白 1 (HINT1) 对于维持运动神经元的正常功能至关重要。因此，一系列人类 HINT1 突变体导致常染色体隐性轴突神经病伴神经肌强直。 HINT1 与信号蛋白建立了一系列调节相互作用，其中一些信号蛋白富含于运动神经元中，例如 1 型 sigma 受体或跨膜 teneurin 1 的细胞内结构域 (ICD)，这两者也与运动障碍有关。在之前的一项研究中，我们报道了 HINT1 从一系列底物中去除小泛素样修饰剂 (SUMO) 的能力以及 HINT1 突变体对此活性的影响。我们现在报道人类 HINT1 突变如何影响 HINT1 与其 SUMO 活性调节剂、钙激活钙调蛋白及其底物 SUMO 的相互作用。此外，HINT1突变体表现出与G蛋白偶联受体（例如mu-阿片类药物）以及谷氨酸N-甲基-D-天冬氨酸受体的异常相互作用。此外，这些 HINT1 突变体表现出与转录调节因子（例如 G 蛋白信号 Z2 蛋白的调节因子和 teneurin 1 的 N 端 ICD 的裂解）的相关性受损。因此，人类 HINT1 突变体的酶活性改变及其与伴侣蛋白的异常相互作用可能与破坏人类运动神经元正常功能所必需的信号通路。