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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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Las quimeras dirigidas a la deubiquitinasa basadas en USP7 estabilizan la AMPK

Jing Liu1,2, Xiaoping Hu3, Kaixiu Luo3

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.

Journal of the American Chemical Society
|April 10, 2024
PubMed
Resumen

Los investigadores desarrollaron nuevas quimeras dirigidas a la deubiquitinasa (DUBTAC) utilizando USP7, expandiendo la estabilización de proteínas dirigidas. Estos DUBTAC basados en USP7 estabilizan eficazmente las proteínas y ofrecen potenciales aplicaciones terapéuticas.

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Área de la Ciencia:

  • La bioquímica
  • Biología molecular
  • Descubrimiento de drogas

Sus antecedentes:

  • Las quimeras dirigidas a la deubiquitinasa (DUBTAC) estabilizan las proteínas, en contraste con la degradación proteica dirigida (TPD).
  • El desarrollo actual de DUBTAC se basa en OTUB1, utilizando ligandos covalentes que pueden afectar la función endógena de OTUB1.

Objetivo del estudio:

  • Explorar USP7 como una deubiquitinasa alternativa para el desarrollo de DUBTAC.
  • Crear y evaluar los DUBTAC basados en el USP7 para la estabilización de proteínas.
  • Investigar los DUBTAC basados en USP7 para estabilizar las isoformas de AMPK.

Principales métodos:

  • Desarrollo de DUBTAC basados en USP7 que utilizan ligandos USP7 no covalentes.
  • Evaluación de los USP7-DUBTAC para la estabilización de la proteína mutante ΔF508-CFTR.
  • Creación de DUBTAC de AMPK utilizando el USP7 y evaluación de la estabilización y señalización de las isoformas de AMPK.

Principales resultados:

  • Los DUBTAC basados en USP7 estabilizaron efectivamente la proteína mutante ΔF508-CFTR, comparable a los DUBTAC basados en OTUB1.
  • Los primeros AMPK DUBTAC se desarrollaron utilizando ligandos no covalentes USP7.
  • Estos nuevos AMPK DUBTAC estabilizaron selectivamente diferentes isoformas de AMPKβ, mejorando la señalización de AMPK.

Conclusiones:

  • USP7 puede utilizarse eficazmente para el desarrollo de DUBTAC, ampliando las opciones más allá de OTUB1.
  • Los ligandos USP7 no covalentes ofrecen una alternativa más segura para la construcción de DUBTAC en comparación con los ligandos OTUB1 covalentes.
  • El desarrollo de AMPK DUBTAC basados en USP7 presenta nuevas vías terapéuticas para modular la señalización de AMPK.