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Switch I and II
Switch I and II are located on MRAS. The switches determine whether MRAS can bind to SHOC2-PP1C. The switches have to go through a conformational change to allow binding of SHOC2-PP1C to MRAS. This conformational change is caused by GTP replacing GDP. Once GTP is added MRAS shifts and binds with SHOC2. When GDP is bound to MRAS switch II is moved outward which causes a steric clash with SHOC2 . When GTP is bound, switch II can form various hydrophobic interactions with SHOC2 . Interactions are strengthened with hydrogen bonding and pi stacking. When MRAS is bound to SHOC2-PP1C, switch I has an important role in making interactions with PP1C.
Binding Pocket
Once all the domains are bound NTpS binds to PP1C in the active site. Once the NTpS is bound it becomes dephosphorylated and the complex falls apart. NTpS is dephosphorylated to prevent the active dimeric RAF from inactivating and changing into its monomeric structure. The NTpS active site is surrounded by hydrophobic and acidic regions. These regions are located on the surface of PP1C whereas the active site is placed further into the structure. It is thought that these regions help the ligand bind to the active site by making interactions that will lead NTpS into the protein. There is still some uncertainty as to how the substrate selectivity works but these regions could play an essential role in it. Specifically, the C-terminal of the pS from NTpS would bind to the hydrophobic region on PP1C.
NTpS can bind to the PP1C active site without PP1C also being bound to SHOC2 and MRAS, however the catalytic activity is much slower and the reaction is less efficient. Also for this event to occur NTpS would need to be exposed from its binding site in the inactive RAF complex. A RAS has to bind to RAF to expose the NTpS allowing PP1C and NTpS to bind.
Relevance
Structural highlights
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