Human HINT1 Mutant Proteins that Cause Axonal Motor Neuropathy Exhibit Anomalous Interactions with Partner Proteins
| Autor: | Pilar Sánchez-Blázquez, Javier Garzón-Niño, María Rodríguez-Muñoz, Elsa Cortés-Montero |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Calmodulin Mutant Neuroscience (miscellaneous) ARAN-NM Nerve Tissue Proteins Protein Structure Secondary 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Regulator of G protein signaling Humans Receptors sigma Amino Acid Sequence Motor Neuron Disease Receptor G protein-coupled receptor biology ICD teneurin 1 Chemistry HINT1 Glutamate receptor Type 1 sigma receptor Tenascin Transmembrane protein Axons Cell biology NMDAR Protein Subunits 030104 developmental biology Neurology SUMO biology.protein Small Ubiquitin-Related Modifier Proteins Mutant Proteins Signal transduction 030217 neurology & neurosurgery RGS Proteins Protein Binding |
| Zdroj: | Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1559-1182 |
| Popis: | 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. This work was supported by Plan Nacional I+D+i [grant number RT-2018-093677-B-100]. |
| Databáze: | OpenAIRE |
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