Video Experimental Relacionado

Updated: Jan 6, 2026

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

Arquitectura de los complejos autoinhibidos y activos BRAF-MEK1-14-3-3

Eunyoung Park^1,2, Shaun Rawson², Kunhua Li^1,2

¹Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

|October 4, 2019

Resumen

Las ideas estructurales revelan cómo las proteínas 14-3-3 regulan la actividad de la BRAF quinasa. Estos hallazgos explican BRAF

Área de la Ciencia:

Biología molecular
Biología estructural
La bioquímica

Sus antecedentes:

Las quinasas RAF, incluida la BRAF, son reguladores clave de la cascada de la MAP que controla el crecimiento celular.
La actividad desregulada de RAF está implicada en varios tipos de cáncer, sin embargo, su regulación estructural sigue sin estar clara.
La comprensión de la regulación BRAF es crucial para el desarrollo de terapias dirigidas contra el cáncer.

Objetivo del estudio:

Elucidar los mecanismos estructurales subyacentes a la autoinhibición y activación de la BRAF quinasa.
Investigar el papel de las proteínas 14-3-3 en la regulación de BRAF.
Proporcionar una base estructural para la comprensión de las mutaciones BRAF en el cáncer.

Principales métodos:

Para determinar las estructuras de alta resolución se empleó la criomicroscopia electrónica (Cryo-EM).
Las estructuras de BRAF de longitud completa se resolvieron en complejo con MEK1 y 14-3-3 dímeros.
El análisis se centró en los estados autoinhibidos y activos de BRAF.

Principales resultados:

Un complejo BRAF-MEK1 autoinhibido es estabilizado por una unión de un dímero 14-3-3 a los sitios BRAF fosforilados.
14-3-3 secuestra los dominios clave de BRAF, impidiendo la dimerización y la actividad de la quinasa.
La activación implica la mediación de la formación de una BRAF quinasa dimérica activa.

Conclusiones:

El 14-3-3 actúa como un andamio crucial, controlando la autoinhibición y la activación de la BRAF quinasa.
Estos hallazgos estructurales ofrecen información sobre la regulación de BRAF y su función aberrante en la enfermedad.
El estudio proporciona un marco para la comprensión de los cánceres y trastornos del desarrollo relacionados con BRAF.

Más Videos Relacionados

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Videos de Conceptos Relacionados

MAPK Signaling Cascades

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...

Assembly of Signaling Complexes

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...

PI3K/mTOR/AKT Signaling Pathway

PI3K/mTOR/AKT Signaling Pathway

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...

mTOR Signaling and Cancer Progression

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...

Amplifying Signals via Enzymatic Cascade

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...

Intracellular Signaling Affects Focal Adhesions

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...