In a study published in Science Advances, Prof. DING Jianping's group at Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences, and Prof. ZHANG Tianlong's group at Shanghai University revealed the molecular mechanism of the S-adenosylmethionine (SAM) sensing of SAMTOR and its functional roles in mechanistic target of rapamycin complex 1 (mTORC1) signaling.
mTORC1 is a major regulator of eukaryotic growth that coordinates cellular anabolic and catabolic processes, and dysfunction of mTORC1 signaling causes a variety of diseases, including obesity, type II diabetes and tumors. Amino acids such as methionine are strong factors that affect mTORC1 activation in eukaryotes.
As a sensor of the methionine derivative SAM, SAMTOR functions upstream of several mTORC1-regulatory complexes, including Rag GTPases, GATOR1, and KICSTOR, and modulates methionine-mediated mTORC1 activation. However, the molecular mechanisms by which SAM signal is transduced to SAMTOR and then promotes the activation or inhibition of mTORC1 are still elusive.
In this work, the researchers determined the crystal structures of Drosophila melanogaster SAMTOR (dSAMTOR) in apo form and in complexes with SAM and SAH and conducted in vitro and in vivo assays to dissect the functional roles of human SAMTOR in the activation of mTORC1 signaling.
In the crystal structures, dSAMTOR is composed of an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. SAM or SAH binds to the MTase domain in a similar manner, and makes extensive hydrophilic and hydrophobic interactions with some conserved residues, while the N-terminal domain is not directly involved in the ligand binding. Interestingly, the ligand binding does not cause significant conformational changes of the MTase domain, and the MTase domain alone has the ability to bind SAM but could not modulate the mTORC1 activity.
The N-terminal helical domain exhibits a high flexibility and acts as the molecular switch in response to SAM/SAH binding. In the absence of SAM/SAH, the helical domain is positioned away from the ligand-binding site, allowing SAMTOR to interact with GATOR1-KICSTOR. The binding of SAM/SAH appears to induce conformational change of the helical domain to cover the ligand-binding site, thus blocking the interaction of SAMTOR with GATOR1-KICSTOR.
The structural and functional data together reveal the molecular mechanism for how SAMTOR senses and binds SAM/SAH and then regulates mTORC1 signaling.
Contact: jpding@sibcb.ac.cn
Reference: https://www.science.org/doi/10.1126/sciadv.abn3868
Appendix：
