Study On The Structure And Function Of Ragulator Protein Complex In MTOR Signaling Pathway

The evolutionarily conserved mTOR signaling pathway can regulate many metabolic processes such as protein synthesis,lipid synthesis,and tive autophagy.And can deregulated cancer,type? diabetes and neurodegeneradisease.As a core member of mTOR signaling pathway,mTORC1 can receive a wide range of intracellular signals such as growth factors,energy,and amino acids.Ragulator complex consists of five subunits: Lamtor1,Lamtor2,Lamtor3,Lamtor4,and Lamtor5(which are also known as p18,p14,MP1,C7orf59,and HBXIP,respectively).The N-terminal region of Lamtor1 contains myristoylation and palmitoylation sites,which anchors the Ragulator complex to the lysosomal membrane.Here,we determined the crystal structure of the Lamtor4-Lamtor5 at2.03(?) resolution and Ragulator complex at 3.01(?) resolution,which shows that Lamtor1 possesses a belt-like shape and wraps the other four subunits around.Extensive hydrophobic interactions occur between Lamtor1 and the Lamtor2-Lamtor3,Lamtor4-Lamtor5 roadblock-domain protein pairs,while there is no substantial contact between Lamtor2-Lamtor3 and Lamtor4-Lamtor5 sub-complexes.Interestingly,an ?-helix from Lamtor1 occupies each of the positions on Lamtor4 and Lamtor5 equivalent to the ?3helices of Lamtor2 and Lamtor3,thus stabilizing Lamtor4 and Lamtor5.Purified Rag A-CTD/Rag C-CTD complex interacted with the Ragulator complex,and mutating or deleting the C-terminal conserved LVVx F motif of Lamtor1 does not affect the interaction between Ragulator and the Rag GTPase complex in vitro.The molecular mechanism of Ragulator recruited Rag GTPase and mTORC1 was introduced from our crystal structure.