Sandbox Reserved 1765: Difference between revisions

== Introduction ==

<scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for MAPK signaling.<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-Ras pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952695/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952695/Pp1cintro/3'>The PP1C subunit</scene> contains the the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> WRITE ABOUT RAF HERE Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref>  

=RAF=

While RAF is not technically part of the SMP protein complex, it is crucial for advancement in the cell signaling pathway SMP helps mediate. RAF plays many different roles in this pathway and has many different domains. RAF has a RAS binding domain (RBD), a N-terminal phosphorylated serine (NTpS), and a kinase domain. Figure ?? shows these domains and mechanistically how RAF is involved in signal advancement and lack thereof. When its N-terminal serine is phosphorylated RAF is bound to a 14-3-3 protein dimer, inactivating the pathway. Whenever the SMP complex is assembled, PP1C dephosphorylates this serine starting the signaling cascade.  

=== Switch I and Switch II ===

SHOC2-PP1C-MRAS is a central gatekeeper in receptor tyrosine kinase signaling 1. 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 figure 2, causes a shift from the open to closed conformation of Switch I. figure 3 Green link The Switch I (SWI) region is made up of residues 42-48 of the MRAS domain. 1 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. Figure 2 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. The closed conformation allows for the binding of SHOC2 and PP1C because there is no steric clash GREEN LINK between the SWI region of MRAS and the surface of SHOC2 when GTP is bound. Green link. The only large-scale conformational change occurs in the MRAS subunit. When GDP is bound to the MRAS domain, it is in the “open” conformation. Green link 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.