Publication: Estudio de la proteína HINT1: actividad SUMO proteasa, regulación de canales TRPs e implicación en el síndrome bipolar y la actividad motora
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2021-07-14
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Universidad Complutense de Madrid
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Abstract
La proteína HINT1 (histidine triad nucleotide-binding protein 1), muy conservada en la filogenia, pertenece a la familia HIT, que se caracteriza por poseer una triada de histidinas que, en varios de sus miembros, está implicada en una actividad hidrolasa aunque, en el caso concreto de la HINT1 se desconocen sus sustratos fisiológicos. A nivel clínico, esta proteína se ha asociado con diversas patologías, particularmente con trastornos psiquiátricos, como la esquizofrenia y el trastorno bipolar, y motores, como la neuropatía axonal recesiva autosómica con neuromiotonía (ARAN-NM), en cuyos pacientes se han descrito 15 mutaciones puntuales recesivas de la HINT1 causantes de esta enfermedad. A nivel celular, la HINT1 se encuentra en membrana plasmática, núcleo y citosol. En la membrana plasmática, la HINT1 actúa como proteína de ensamblaje y/o chaperona interaccionando con una amplia variedad de proteínas de señalización, entre los que cabe destacar los reguladores de la señalización de las proteínas G (RGS) y los receptores de glutamato NMDA, además de ser esencial en la regulación funcional de varios receptores acoplados a proteínas G. En el núcleo, la HINT1 juega un papel importante como represor transcripcional asociándose con diferentes factores de transcripción, como el complejo Pontin/Reptin y el dominio intracelular (ICD) de la teneurina 1. Además, la HINT1 es una proteína supresora de tumores ya que participa en la respuesta al daño del ADN, promueve la apoptosis e inhibe la proliferación de células en diversos cánceres...
The phylogenetically highly conserved histidine triad nucleotide-binding protein 1 (HINT1) belongs to the HIT family, which is characterized by a histidine triad involved in hydrolase activity in several of its members, although the physiological substrates of HINT1 are unknown. At the clinical level, HINT1 has been related to various pathologies, especially with psychiatric disorders, such as schizophrenia and bipolar disorder, and motor disorders, such as autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), in whose patients 15 recessive point mutations of HINT1 have been described causing this disease. At the cellular level, HINT1 is found in the plasma membrane, nucleus, and cytosol. At the plasma membrane, HINT1 acts as an assembly and/or chaperone protein interacting with a wide variety of signaling proteins, including regulators of G protein signaling (RGS) and NMDA glutamate receptors, as well as being essential in the functional regulation of several G protein-coupled receptors. In the nucleus, HINT1 plays an important role as a transcriptional repressor by associating with different transcription factors, such as the Pontin/Reptin complex and the intracellular domain (ICD) of teneurin 1. In addition, HINT1 is considered a tumor suppressor protein as it participates in the DNA damage response, promotes apoptosis and inhibits cell proliferation in various cancers...
The phylogenetically highly conserved histidine triad nucleotide-binding protein 1 (HINT1) belongs to the HIT family, which is characterized by a histidine triad involved in hydrolase activity in several of its members, although the physiological substrates of HINT1 are unknown. At the clinical level, HINT1 has been related to various pathologies, especially with psychiatric disorders, such as schizophrenia and bipolar disorder, and motor disorders, such as autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), in whose patients 15 recessive point mutations of HINT1 have been described causing this disease. At the cellular level, HINT1 is found in the plasma membrane, nucleus, and cytosol. At the plasma membrane, HINT1 acts as an assembly and/or chaperone protein interacting with a wide variety of signaling proteins, including regulators of G protein signaling (RGS) and NMDA glutamate receptors, as well as being essential in the functional regulation of several G protein-coupled receptors. In the nucleus, HINT1 plays an important role as a transcriptional repressor by associating with different transcription factors, such as the Pontin/Reptin complex and the intracellular domain (ICD) of teneurin 1. In addition, HINT1 is considered a tumor suppressor protein as it participates in the DNA damage response, promotes apoptosis and inhibits cell proliferation in various cancers...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Farmacología y Toxicología, leída el 29/04/2021