Human HINT1 Mutant Proteins that Cause Axonal Motor Neuropathy Exhibit Anomalous Interactions with Partner Proteins

被引:5
作者
Cortes-Montero, Elsa [1 ]
Rodriguez-Munoz, Maria [1 ]
Sanchez-Blazquez, Pilar [1 ]
Garzon-Nino, Javier [1 ]
机构
[1] CSIC, Dept Translat Neurosci, Inst Cajal, Neuropharmacol, Madrid, Spain
关键词
HINT1; ARAN-NM; Type 1 sigma receptor; SUMO; NMDAR; ICD teneurin 1; TRANSFER-RNA SYNTHETASE; CENTRAL-NERVOUS-SYSTEM; OF-FUNCTION MUTATIONS; SIGMA-1; RECEPTOR; TUMOR-SUPPRESSOR; ENDOPLASMIC-RETICULUM; THERAPEUTIC TARGET; BINDING-SITES; FAMILY; REGULATOR;
D O I
10.1007/s12035-020-02265-x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1834 / 1845
页数:12
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