Sandbox Reserved 1767: Difference between revisions

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=== PP1C ===

[[Image:CS.png|300 px|right|thumb|'''Figure 2:''' Catalytic Site of PP1C (PDB 7DSO) <ref name="Liau">PMID: 35768504</ref>.]]

<scene name='95/952695/Pp1cintro/3'>The Protein Phosphatase Complex 1 (PP1C)</scene> subunit contains the catalytic site of the SMP complex. PP1C is a [https://pubmed.ncbi.nlm.nih.gov/30036567/. Phosphatase] enzyme responsible for the removal of a phosphate group on the N-terminal phosphoserine (NTpS) of RAF (Ser259)<ref name="Liau">PMID: 35768504</ref>. The exact mechanism of dephosphorylation is currently unknown, but there are three catalytic metal ions: 2 Mn⁺² and 1 Cl⁻¹ present that coordinate [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458771/. nucleophilic] water molecules in the active site <ref name="Hauseman">PMID:35830882</ref>. This dephosphorylation event allows for pathway activation <ref name="Liau">PMID: 35768504</ref>. Although PP1C can dephosphorylate other proteins independently from the SMP complex, it cannot act on RAF unless bound to the complex because it lacks intrinsic substrate selectivity <ref name="Liau">PMID: 35768504</ref>. SHOC2 and MRAS aid in the specificity of the enzymatic activity. PP1C binds to SHOC2 and MRAS-GTP in a specific orientation that doesn’t change the conformation of the catalytic site and leaves it accessible for substrate binding as shown in '''Figure 2''' in red.

<scene name='95/952695/Pp1cintro/3'>The Protein Phosphatase Complex 1 (PP1C)</scene> subunit contains the catalytic site of the SMP complex. PP1C is a [https://pubmed.ncbi.nlm.nih.gov/30036567/. Phosphatase] enzyme responsible for the removal of a phosphate group on the N-terminal phosphoserine (NTpS) of RAF (Ser259)<ref name="Liau">PMID: 35768504</ref>. The exact mechanism of dephosphorylation is currently unknown, but there are three catalytic metal ions: 2 Mn⁺² and 1 Cl⁻¹ present that coordinate [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458771/. nucleophilic] water molecules in the active site <ref name="Hauseman">PMID:35830882</ref>. This dephosphorylation event allows for pathway activation <ref name="Liau">PMID: 35768504</ref>. Although PP1C can dephosphorylate other proteins independently from the SMP complex, it cannot act on RAF unless bound to the complex because it lacks intrinsic substrate selectivity <ref name="Liau">PMID: 35768504</ref>. SHOC2 and MRAS aid in the specificity of the enzymatic activity. PP1C binds to SHOC2 and MRAS-GTP in a specific orientation that doesn’t change the conformation of the {{Font color|red|catalytic site}} and leaves it accessible for substrate binding as shown in '''Figure 2''' in red.

PP1C binds to SHOC2 through a hydrophobic N-terminal disordered region that is complimentary to the <scene name='95/952695/Rvxf_motif/2'>RVXF Motif on SHOC2</scene> and adjacent to a catalytic metal ions <ref name="Liau">PMID: 35768504</ref>. In the RAS/RAF signaling cascade, the region of RAF that is C-terminal to the phosphate group binds to this hydrophobic groove, and the remaining residues bind to the hydrophobic region of SHOC2 <ref name="Hauseman">PMID:35830882</ref>. RAF binding to this region of SHOC2 is what allows PP1C to be specific when in the SMP complex in comparison to PP1C on its own <ref name="Hauseman">PMID:35830882</ref>. Similarly to SHOC2, PP1C does not undergo a <scene name='95/952694/Pp1coverlay/4'>significant conformational change</scene> when SHOC2 and MRAS-GTP bind. The lack of conformational change shows that the structure of PP1C is not dependent on the SMP complex, but in order to act as a phosphatase it must be bound to the complex <ref name="Liau">PMID: 35768504</ref>.

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RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. intracellular switches] that are anchored to the plasma membrane. <ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane allowing only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <ref name="Hauseman">PMID:35830882</ref>.

A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''', {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2}} ~~binding site~~ colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|RAF binding site}} shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway <ref name="Lavoie">PMID: 35970881</ref>. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</scene> is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane.

A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''', {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2 binding site}} colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|RAF binding site}} shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway <ref name="Lavoie">PMID: 35970881</ref>. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</scene> is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane.

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[[Image:RASRAF.png|410 px|right|thumb|'''Figure 5''': 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 <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, shown in '''Figure 4''', a conformational change occurs. This change', 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058769/. 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>.

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, shown in '''Figure 4''', a conformational change occurs. This change 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058769/. 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>.

=== Cancer and Rasopathies ===

Sandbox Reserved 1767: Difference between revisions

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@@ Line 20: / Line 20: @@
 === PP1C ===
 [[Image:CS.png|300 px|right|thumb|'''Figure 2:''' Catalytic Site of PP1C (PDB 7DSO) <ref name="Liau">PMID: 35768504</ref>.]]
-<scene name='95/952695/Pp1cintro/3'>The Protein Phosphatase Complex 1 (PP1C)</scene> subunit contains the catalytic site of the SMP complex. PP1C is a [https://pubmed.ncbi.nlm.nih.gov/30036567/. Phosphatase] enzyme responsible for the removal of a phosphate group on the N-terminal phosphoserine (NTpS) of RAF (Ser259)<ref name="Liau">PMID: 35768504</ref>. The exact mechanism of dephosphorylation is currently unknown, but there are three catalytic metal ions: 2 Mn⁺² and 1 Cl⁻¹ present that coordinate [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458771/. nucleophilic] water molecules in the active site <ref name="Hauseman">PMID:35830882</ref>. This dephosphorylation event allows for pathway activation <ref name="Liau">PMID: 35768504</ref>. Although PP1C can dephosphorylate other proteins independently from the SMP complex, it cannot act on RAF unless bound to the complex because it lacks intrinsic substrate selectivity <ref name="Liau">PMID: 35768504</ref>. SHOC2 and MRAS aid in the specificity of the enzymatic activity. PP1C binds to SHOC2 and MRAS-GTP in a specific orientation that doesn’t change the conformation of the catalytic site and leaves it accessible for substrate binding as shown in '''Figure 2''' in red.
+<scene name='95/952695/Pp1cintro/3'>The Protein Phosphatase Complex 1 (PP1C)</scene> subunit contains the catalytic site of the SMP complex. PP1C is a [https://pubmed.ncbi.nlm.nih.gov/30036567/. Phosphatase] enzyme responsible for the removal of a phosphate group on the N-terminal phosphoserine (NTpS) of RAF (Ser259)<ref name="Liau">PMID: 35768504</ref>. The exact mechanism of dephosphorylation is currently unknown, but there are three catalytic metal ions: 2 Mn⁺² and 1 Cl⁻¹ present that coordinate [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458771/. nucleophilic] water molecules in the active site <ref name="Hauseman">PMID:35830882</ref>. This dephosphorylation event allows for pathway activation <ref name="Liau">PMID: 35768504</ref>. Although PP1C can dephosphorylate other proteins independently from the SMP complex, it cannot act on RAF unless bound to the complex because it lacks intrinsic substrate selectivity <ref name="Liau">PMID: 35768504</ref>. SHOC2 and MRAS aid in the specificity of the enzymatic activity. PP1C binds to SHOC2 and MRAS-GTP in a specific orientation that doesn’t change the conformation of the {{Font color|red|catalytic site}} and leaves it accessible for substrate binding as shown in '''Figure 2''' in red.
 PP1C binds to SHOC2 through a hydrophobic N-terminal disordered region that is complimentary to the <scene name='95/952695/Rvxf_motif/2'>RVXF Motif on SHOC2</scene> and adjacent to a catalytic metal ions <ref name="Liau">PMID: 35768504</ref>.  In the RAS/RAF signaling cascade, the region of RAF that is C-terminal to the phosphate group binds to this hydrophobic groove, and the remaining residues bind to the hydrophobic region of SHOC2 <ref name="Hauseman">PMID:35830882</ref>. RAF binding to this region of SHOC2 is what allows PP1C to be specific when in the SMP complex in comparison to PP1C on its own <ref name="Hauseman">PMID:35830882</ref>. Similarly to SHOC2, PP1C does not undergo a <scene name='95/952694/Pp1coverlay/4'>significant conformational change</scene> when SHOC2 and MRAS-GTP bind. The lack of conformational change shows that the structure of PP1C is not dependent on the SMP complex, but in order to act as a phosphatase it must be bound to the complex <ref name="Liau">PMID: 35768504</ref>.
@@ Line 34: / Line 34: @@
 RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. intracellular switches] that are anchored to the plasma membrane. <ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane allowing only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <ref name="Hauseman">PMID:35830882</ref>.
-A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''',  {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2}} binding site colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|RAF binding site}} shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway <ref name="Lavoie">PMID: 35970881</ref>. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</scene> is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane.
+A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''',  {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2 binding site}} colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|RAF binding site}} shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway <ref name="Lavoie">PMID: 35970881</ref>. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</scene> is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane.
@@ Line 44: / Line 44: @@
 [[Image:RASRAF.png|410 px|right|thumb|'''Figure 5''': 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 <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, shown in '''Figure 4''', a conformational change occurs. This change', 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058769/. 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>.
+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, shown in '''Figure 4''', a conformational change occurs. This change 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058769/. 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>.
 === Cancer and Rasopathies ===