Sandbox Reserved 1767: Difference between revisions
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SHOC2 is essential for complex formation, however SHOC2 only undergoes a 6° <scene name='95/952693/Shoc2_gtp_bound_vs_gdp_bound/7'>conformational change</scene> when MRAS and PP1C bind.<ref name="Hauseman">PMID:35830882</ref> SHOC2 is just the place where MRAS and PP1C come together. SHOC2 and PP1C first engage in binding with each other, and MRAS-GTP binds, stabilizing SHOC2 and PP1C binding, and fully forming the SHOC2-MRAS-PP1C holophophatase complex. <ref name="Kwon">PMID: 35831509</ref> | SHOC2 is essential for complex formation, however SHOC2 only undergoes a 6° <scene name='95/952693/Shoc2_gtp_bound_vs_gdp_bound/7'>conformational change</scene> when MRAS and PP1C bind.<ref name="Hauseman">PMID:35830882</ref> SHOC2 is just the place where MRAS and PP1C come together. SHOC2 and PP1C first engage in binding with each other, and MRAS-GTP binds, stabilizing SHOC2 and PP1C binding, and fully forming the SHOC2-MRAS-PP1C holophophatase complex. <ref name="Kwon">PMID: 35831509</ref> | ||
=== PP1C === | === PP1C === | ||
SHOC2 has a RVxF binding motif that interacts with the PP1C RVxF binding site. The N-terminal loop of SHOC2 interacts with the RVxF binding site of PP1C, highlighting the structure and function connection of the complex. RVxF allows PP1C substrates to bind, whereas RAF has the RVxF motif, so it can bind to the hydrophobic region of SHOC2, allowing for greater specificity. Additionally, PP1C and SHOC2 do not change conformationally upon the binding of GTP, but rather they are inactive when RAS is bound to GDP due to steric strain. <scene name='95/952694/Pp1coverlay/ | SHOC2 has a RVxF binding motif that interacts with the PP1C RVxF binding site. The N-terminal loop of SHOC2 interacts with the RVxF binding site of PP1C, highlighting the structure and function connection of the complex. RVxF allows PP1C substrates to bind, whereas RAF has the RVxF motif, so it can bind to the hydrophobic region of SHOC2, allowing for greater specificity. Additionally, PP1C and SHOC2 do not change conformationally upon the binding of GTP, but rather they are inactive when RAS is bound to GDP due to steric strain. <scene name='95/952694/Pp1coverlay/3'>PP1C retains the same structure</scene> with or without binding to the SMP complex as PP1C retains its enzymatic function independently.<ref name="Liau">PMID: 35768504</ref>. | ||
=== MRAS === | === MRAS === | ||
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[[Image:Table.jpeg|350 px|left|thumb|Figure 1. Residues Interacting at SWI and SWII at subunits SHOC2 and PP1C.<ref name="Liau">PMID: 35768504</ref>.]] | [[Image:Table.jpeg|350 px|left|thumb|Figure 1. Residues Interacting at SWI and SWII at subunits SHOC2 and PP1C.<ref name="Liau">PMID: 35768504</ref>.]] | ||
Switch I (SWI) and Switch II (SWII) are located between the SHOC2 and MRas subunits. When GTP is hydrolyzed to GDP, Switch I and Switch II relax, in the relaxed state SHOC2 cannot bind to MRas. Two Residues from MRas interact with the gamma phosphate on GTP, changing the complex to the closed confirmation. When GTP is bound to <scene name='95/952694/Mras_switch_i/ | Switch I (SWI) and Switch II (SWII) are located between the SHOC2 and MRas subunits. When GTP is hydrolyzed to GDP, Switch I and Switch II relax, in the relaxed state SHOC2 cannot bind to MRas. Two Residues from MRas interact with the gamma phosphate on GTP, changing the complex to the closed confirmation. When GTP is bound to <scene name='95/952694/Mras_switch_i/6'>MRAS at SWI</scene>, it triggers the assembly of the SHOC2 Complex. When SWI is in its open confirmation, PP1C cannot bind with MRas due to the steric clashes, but when GTP binds and SWI is in its closed confirmation, PP1C can bind without hinderance. In a mutated complex, other RAS proteins can replace MRas making cell proliferation more likely. SHOC2-PP1C-MRas may be used as a therapeutic target for cancer treatments through changing the confirmation of the <scene name='95/952694/Mrasswitchii/2'>RAS at SWII</scene>. | ||
=== Ras/Raf === | === Ras/Raf === | ||