Video Experimental Relacionado
Updated: May 28, 2026
10:44
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Los antagonistas inducen un cambio conformacional en cIAP1 que promueve la autobiquitinación
Erin C Dueber1, Allyn J Schoeffler, Andreas Lingel
1Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Science (New York, N.Y.)
|October 25, 2011
Resumen
Las proteínas inhibidoras de la apoptosis (IAP) regulan la muerte celular. La unión del antagonista a las proteínas celulares IAP (cIAP) induce la dimerización de RING, activando la actividad de la E3 ligasa y promoviendo la muerte celular.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Regulación de la muerte celular.
Sus antecedentes:
- Las proteínas inhibidoras de la apoptosis (IAP) son reguladores negativos clave de la muerte celular programada.
- Los miembros de la familia IAP poseen actividad de E3 ubiquitina ligasa a través de sus dominios RING.
- El antagonista que se une a los dominios de repetición del baculovirus IAP (BIR) de las proteínas celulares IAP (cIAP) desencadena la degradación y la apoptosis.
- El mecanismo por el cual la unión de antagonistas afecta la actividad del dominio RING sigue sin estar claro.
Objetivo del estudio:
- Aclarar los mecanismos estructurales y bioquímicos por los cuales la unión de antagonistas a las proteínas cIAP influye en la actividad de la E3 ligasa.
- Comprender cómo la actividad del dominio RING está regulada por la estructura general de cIAP.
Principales métodos:
- Ensayos bioquímicos para estudiar las interacciones de proteínas y la actividad enzimática.
- Estudios estructurales, que probablemente incluyan cristalografía de rayos X o cryo-EM, para determinar las conformaciones de las proteínas.
Principales resultados:
- El cIAP1 no ligado existe como un monómero compacto, secuestrando el dominio RING y evitando su dimerización.
- La unión de antagonistas induce cambios conformacionales dentro de la cIAP1.
- Estas reorganizaciones facilitan la dimerización del dominio RING, lo que lleva a la formación de un complejo de ligasa de ubiquitina E3 activo.
Conclusiones:
- La unión del antagonista es un evento alostérico crítico que alivia la autoinhibición de la actividad de la ligasa cIAP1 E3.
- Los hallazgos revelan un nuevo mecanismo de activación de la E3 ligasa a través de cambios conformacionales inducidos y dimerización.
- Esto proporciona una comprensión más profunda de la regulación de la proteína IAP y la posible orientación terapéutica.
Videos de Conceptos Relacionados
00:50Anaphase Promoting Complex
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
02:58Regulated Protein Degradation
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.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
02:04Covalently Linked Protein Regulators
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.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.
01:13The Proteasome
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.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
02:18The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...