Understanding the role of mTOR-mLst8 binding through coarse-grained simulation approaches

ABSTRACT

The kinase called mechanistic Target of Rapamycin (mTOR) belongs to a complex network pathway responsible for many physiological mechanisms, responses to multiple factors and usually is deregulated in various types of diseases. In vitro studies support the idea that the binding of mammalian lethal with SEC13 protein 8 (mLst8) subunit on mTOR is necessary to initiate the kinase phosphotransference process. Thus, the mLst8 subunit is important for the regulation of mTOR complex, but its function, especially on catalytic site, needs to be defined. In addition, the contribution of mLst8 to the development and control of pathologies, particularly those in which the mTOR pathways seems deregulated, remains unsolved or with few available data and could be an important step to develop new strategies avoiding the superexpression of this pathway. In our study, we employed coarse-grained molecular dynamics simulation to analyse the behaviour of the mTOR catalytic site when the subunit mLst8 is associated or not, providing insights about the importance of mTOR-mLst8 interaction for the kinase mechanism.

GRAPHICAL ABSTRACT

KEYWORDS:

• Mechanistic target of rapamycin
• coarse-grained simulation
• mTOR-mLst8 interaction
• catalytic site stabilization

Acknowledgements

We would like to acknowledge the team from Laboratorio de Simulaciones Biomoleculares of Institut Pasteur de Montevideo and Fernando Vieira Lazzarin.

Disclosure statement

No potential conflict of interest was reported by the author(s).