Sandbox Reserved 1767: Difference between revisions

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[[Image:RASRAF.png|400 px|right|thumb|Figure 2: MRAS SWI and SWII open and closed conformations.<ref name="Liau">PMID: 35768504</ref>.]]

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, shown in 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. 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.

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, shown in figure 2, 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. fThe 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. 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, as seen in figure 2. 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. 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. 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.

=== Cancer and Rasopathies === should we intersperse this?

===Cancer and Rasopathies=== should we intersperse this?

Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</ref> Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. Mutations in PP1C can trigger increased active site activity, increasing the RAF proteins that are active and available to bind to RAS. Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to cancer and/or RASopathies.

Sandbox Reserved 1767: Difference between revisions

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@@ Line 43: / Line 43: @@
 [[Image:RASRAF.png|400 px|right|thumb|Figure 2: MRAS SWI and SWII open and closed conformations.<ref name="Liau">PMID: 35768504</ref>.]]
-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, shown in 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. 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.
+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, shown in figure 2, 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. fThe 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. 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, as seen in figure 2. 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. 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. 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.
-=== Cancer and Rasopathies === should we intersperse this?
+===Cancer and Rasopathies=== should we intersperse this?
 Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</ref> Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. Mutations in PP1C can trigger increased active site activity, increasing  the RAF proteins that are active and available to bind to RAS. Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to cancer and/or RASopathies.