Sandbox Reserved 1767: Difference between revisions

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<scene name='95/952695/Shoc2intro/1'>SHOC2</scene> is essential for complex formation. It is a crescent shaped complex that serves as a bridge for PP1C and MRAS, maximizing interaction between the three subunits of the SMP complex <ref name="Hauseman">PMID:35830882</ref>. SHOC2 contains a large leucine rich region (LRR) that provides stability and localizes subunit PP1C to the membrane<ref name="Liau">PMID: 35768504</ref>. SHOC2 only undergoes a <scene name='95/952693/Shoc2_gtp_bound_vs_gdp_bound/7'>6° conformational change</scene> when PP1C and MRAS bind showing it is a scaffolding protein that provides a favorable interface for complex formation<ref name="Liau">PMID: 35768504</ref>. SHOC2 depletion is being studied as a therapeutic approach for RAS-driven cancers due to large scale interactions of the subunits being made possible by SHOC2 <ref name="Kwon">PMID: 35831509</ref>. As shown in '''Figure 1 '''SHOC2 and PP1C first engage in binding with each other via an N-terminal <scene name='95/952695/Rvxf_motif/2'>RVXF Motif</scene> on SHOC2 that is complimentary to a binding sequence on PP1C. SHOC2 residues <scene name='95/952695/Shoc2_highlighted_residues/1'>V64 and F66</scene> embed in the complimentary region of PP1C, enhancing SHOC2 affinity for PP1C. SHOC2 binds MRAS-GTP through β strands of a LRR that interacts with a [https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook_Maps/Supplemental_Modules_(Physical_and_Theoretical_Chemistry)/Physical_Properties_of_Matter/Atomic_and_Molecular_Properties/Intermolecular_Forces/Hydrophobic_Interactions. hydrophonic] region of MRAS-GTP further stabilizing the complex<ref name="Kwon">PMID: 35831509</ref>.

=== PP1C ===

<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://en.wikipedia.org/wiki/Phosphatase. 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 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.''' ~~SHOW IN 2D SURFACE IMAGE~~'''

[[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://en.wikipedia.org/wiki/Phosphatase. 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 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'''.

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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 <scene name='95/952695/Shoc2intro/1'>SHOC2</scene> is essential for complex formation. It is a crescent shaped complex that serves as a bridge for PP1C and MRAS, maximizing interaction between the three subunits of the SMP complex <ref name="Hauseman">PMID:35830882</ref>. SHOC2 contains a large leucine rich region (LRR) that provides stability and localizes subunit PP1C to the membrane<ref name="Liau">PMID: 35768504</ref>. SHOC2 only undergoes a <scene name='95/952693/Shoc2_gtp_bound_vs_gdp_bound/7'>6° conformational change</scene> when PP1C and MRAS bind showing it is a scaffolding protein that provides a favorable interface for complex formation<ref name="Liau">PMID: 35768504</ref>. SHOC2 depletion is being studied as a therapeutic approach for RAS-driven cancers due to large scale interactions of the subunits being made possible by SHOC2 <ref name="Kwon">PMID: 35831509</ref>. As shown in '''Figure 1 '''SHOC2 and PP1C first engage in binding with each other via an N-terminal <scene name='95/952695/Rvxf_motif/2'>RVXF Motif</scene> on SHOC2 that is complimentary to a binding sequence on PP1C. SHOC2 residues <scene name='95/952695/Shoc2_highlighted_residues/1'>V64 and F66</scene> embed in the complimentary region of PP1C, enhancing SHOC2 affinity for PP1C. SHOC2 binds MRAS-GTP through β strands of a LRR that interacts with a [https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook_Maps/Supplemental_Modules_(Physical_and_Theoretical_Chemistry)/Physical_Properties_of_Matter/Atomic_and_Molecular_Properties/Intermolecular_Forces/Hydrophobic_Interactions. hydrophonic] region of MRAS-GTP further stabilizing the complex<ref name="Kwon">PMID: 35831509</ref>.
 === PP1C ===
-<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://en.wikipedia.org/wiki/Phosphatase. 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 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.''' SHOW IN 2D SURFACE IMAGE'''
+[[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://en.wikipedia.org/wiki/Phosphatase. 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 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'''.
 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>.