Although a few cellular AA sensors have been recently reported, their sensing mechanism and function are idiosyncratic and it is not well known whether and how they are communicated. Considering the importance in the balance of all 20 AAs for protein synthesis and metabolism, cells might have a molecular system that can coordinate AA-dependent protein synthesis with signal pathways and metabolism in an integrated manner.
Multi-tRNA synthetase complex (MSC)
Aminoacyl-tRNA synthetases (ARSs) are the essential enzymes catalyzing the covalent linkage of their specific AAs to tRNAs for protein synthesis. With their capability of recognizing specific AAs, they might have a potential to work as specific AA sensors.
In mammals, ARSs are classified into free and complex-bound forms, and the latter are components of the multi-tRNA synthetase complex (MSC). MSC is expected to form bisymmetric structure composed of 8 ARSs for 9 AAs (EP, I, L, M, Q, K, R, D) and 3 scaffold proteins (AIMP1-3).
This research was aimed to address the question whether ARSs would generally work as AA sensors, particularly focusing on an intriguing macromolecular complex, MSC.
Schematic model of ARS sensosome to decode nine AA-sensing mechanisms.
Intracellular AA levels are determined by amino acid uptake, export, biosynthesis and degradation. Since AA levels should be tightly balanced for efficient protein synthesis and body homeostasis, the cellular levels of twenty (or a portion) AA is expected to be sensed by their corresponding ARSs. Among ARSs, eight different ARSs (marked pink) form a macromolecular protein complex, MSC, sensing their substrate AAs in an integrated mode although it is not known yet whether the MSC-forming ARSs would also make communication with the remaining ARSs (marked blue). MSC would thus coordinate AA-dependent protein synthesis and signal pathways, leading to control AA and energy metabolism and to determine cell phenotype. These functions may in turn affect the levels of AAs and activities of ARSs through feedback regulation.
Amino Acid sensosome
The main objective of this research is to validate the function of MSC as an integrated AA sensory machinery (“AA sensosome”). The research outcome will newly define the canonical function of ARSs as AA sensors in addition to their catalysis for protein synthesis, and suggest MSC as an integrated AA sensory machinery. Since the previously reported AA sensors have been individually studied as a discrete functional unit for a specific AA, our research outcome will provoke a paradigm shift of AA sensing mechanism to more systematic perspectives.
Moreover, the research will be further conducted to understand the AA sensing mechanisms of the component ARSs and to evaluate its pathophysiological significance, particularly focusing on cancer biology.