RESUMEN
The phosphatidylinositol 3-kinase related protein kinases (PIKKs) are key to the regulation of a variety of eukaryotic cellular processes including DNA repair and growth regulation. While these massive proteins had long resisted structural analysis, recent advances in electron cryo-microscopy have now facilitated structural analysis of the major examples of PIKKs, including mTOR, DNA-PK, ATM, ATR and TRAPP/Tra1. In these PIKKs, the carboxy-terminal kinase domains and their proximal regions are structurally conserved. The structural organization of their extensive amino-terminal repeat regions, however, as well as their oligomeric organization and their interactions with accessory proteins, differ markedly amongst PIKKs. This architectural divergence provides the structural basis for the complex regulatory roles and functional diversity of PIKKs.
Asunto(s)
Fosfatidilinositol 3-Quinasa/química , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Cromatina/química , Humanos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Subunidades de Proteína , Secuencias Repetitivas de Aminoácido , Sirolimus/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex.
