Evolutionary Conservation of the Components in the TOR Signaling Pathways.

Hisashi Tatebe,Kazuhiro Shiozaki

doi:10.3390/biom7040077

Abstract

Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that controls multiple cellular processes upon various intracellular and extracellular stimuli. Since its first discovery, extensive studies have been conducted both in yeast and animal species including humans. Those studies have revealed that TOR forms two structurally and physiologically distinct protein complexes; TOR complex 1 (TORC1) is ubiquitous among eukaryotes including animals, yeast, protozoa, and plants, while TOR complex 2 (TORC2) is conserved in diverse eukaryotic species other than plants. The studies have also identified two crucial regulators of mammalian TORC1 (mTORC1), Ras homolog enriched in brain (RHEB) and RAG GTPases. Of these, RAG regulates TORC1 in yeast as well and is conserved among eukaryotes with the green algae and land plants as apparent exceptions. RHEB is present in various eukaryotes but sporadically missing in multiple taxa. RHEB, in the budding yeast Saccharomyces cerevisiae, appears to be extremely divergent with concomitant loss of its function as a TORC1 regulator. In this review, we summarize the evolutionarily conserved functions of the key regulatory subunits of TORC1 and TORC2, namely RAPTOR, RICTOR, and SIN1. We also delve into the evolutionary conservation of RHEB and RAG and discuss the conserved roles of these GTPases in regulating TORC1.

Highlights

Target of rapamycin (TOR) is a phosphoinositide-3 kinase-related protein kinase that plays pivotal roles in controlling a wide variety of cellular processes in response to a broad spectrum of intracellular and extracellular stimuli [1]
DEPDC5: DEP domain containing 5; NPRL2: nitrogen permease regulator 2-like protein; NPRL3: nitrogen permease regulator 3-like protein; RAPTOR: regulatory associated protein of mTOR; RHEB: Ras homolog enriched in brain; RICTOR: rapamycin-insensitive companion of mTOR; SIN1: stress-activated protein kinase interacting protein 1; TOR: target of rapamycin; TSC1, 2: tuberous sclerosis complex 1, 2
RAG have been emerging as critical regulators of mammalian TOR complex 1 (TORC1), we review the molecular functions of RAPTOR, RICTOR, and SIN1 subunits, with emphasis on their structures

Summary

Introduction

Target of rapamycin (TOR) is a phosphoinositide-3 kinase-related protein kinase that plays pivotal roles in controlling a wide variety of cellular processes in response to a broad spectrum of intracellular and extracellular stimuli [1]. In the crystal structures of the C-terminal half of human TOR, the kinase bottom of the cleft active and sterically hindered by the surrounding domain is deep in an catalytic enzymatically conformation [7]. Considering the significant homologies throughout the N-terminal HEAT repeat that the characteristic solenoid structures as well as the two-fold symmetric ring formation are very region of TOR, it is expected that the characteristic solenoid structures as well as the two-fold common amongring orthologs. We summarize and discuss the same catalytic subunit TOR kinase and a regulator subunit called LST8 (Figure 3), and the physiological evolutionarily conserved molecular functions of RAPTOR, RICTOR, and SIN1 subunits, with and biochemical distinction of the two complexes is mainly determined by the complex-specific emphasis on their structures. Throughout this review, we utilize human protein names without the prefixes “m” (for mammal) or “h” (for human) to describe each component in the TOR signaling pathways [14]

Composition and regulationofofTORC1

TORC2 and Two Key Regulatory Subunits

RHEB and TSC

A phylogram of of RHEB

The RAG GTPases and Their GAP Complex GATOR1