Sandbox Reserved 1767: Difference between revisions

SHOC2-PP1C-MRAS is a central gatekeeper in receptor tyrosine kinase signaling <ref name="Liau">PMID: 35768504</ref>. '''Figure 1''' shows the specific pathways SHOC2-PP1C-MRAS mediates. When MRAS is bound to GDP, shown in the left of '''Figure 1''', RAF is bound to a 14-3-3 protein dimer restricting it to the cytoplasm. When MRAS-GDP is exchanged for GTP via a nucleotide exchange factor GEF, a conformational change occurs. This change, shown in '''Figure 4''', causes a shift from the <scene name='95/952693/Swi_open_conformation/6'>open conformation</scene> to <scene name='95/952693/Switch_i_gtp_bound/11'>closed conformation</scene> of Switch I, shown in '''Figure 5'''. The Switch I (SWI) region is made up of residues 42-48 of the MRAS domain <ref name="Kwon">PMID: 35831509</ref>. These residues are crucial for the binding of MRAS, SHOC2, and PP1C because MRAS undergoes a conformational change that allows for SMP complex assembly upon GTP binding <ref name="Hauseman">PMID:35830882</ref>. When GTP is bound to MRAS, it is in the “closed conformation” because hydrogen bond interactions between the γ phosphate of GTP and residues in the SWI region of MRAS cause SWI to adopt a closed conformation <ref name="Hauseman">PMID:35830882</ref>, as seen in '''Figure 5'''. The closed conformation allows for the binding of SHOC2 and PP1C because there is no steric clash between the <scene name='95/952693/Switch_i_gtp_bound/11'>SWI region of MRAS</scene> and the surface of SHOC2 when GTP is bound <ref name="Kwon">PMID: 35831509</ref>. The only large-scale conformational change occurs in the MRAS subunit <ref name="Liau">PMID: 35768504</ref>. When GDP is bound to the MRAS domain, it is in the “open” conformation. Since the γ-phosphate is not bound to GDP, there are no hydrogen bond interactions with the oxygens of the γ-phosphate group and the MRAS SWI region, causing MRAS to adpot an "open" conformation. Since SHOC2 and PP1C do not undergo much conformational change, they are in a slow equilibrium of binding and unbinding until MRAS binds to GTP allowing MRAS to bind to SHOC2 and PP1C <ref name="Liau">PMID: 35768504</ref>.