Sandbox Reserved 1788: Difference between revisions
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= Introduction = | = Introduction = | ||
[[Image:SMP complex.jpg|300 px|right|thumb|'''Figure 1:'''Overall cartoon of SHOC2-PP1C-MRAS structure with SHOC2 in pink, PP1C in blue, and MRAs in white.</div></font>]] | [[Image:SMP complex.jpg|300 px|right|thumb|'''Figure 1:'''Overall cartoon of SHOC2-PP1C-MRAS structure with SHOC2 in pink, PP1C in blue, and MRAs in white.</div></font>]] | ||
<scene name='95/ | <scene name='95/952716/Zoom_out/1'>SHOC2-PP1C-MRAS</scene> (SMP) is a ternary holoposphatase complex formed by the individual proteins: SHOC2, PP1C, and MRAS. Formation of this complex begins with a signal binding to a receptor tyrosine kinase receptor(RTK). This causes membrane-bound MRAS to exchange GDP for GTP. From here the complex comes together in the plasma membrane. Its role in MAPK signaling is the dephosphorylation of the N-terminal phosphoserine (NTpS) on the RAF complex leading to further downstream signaling effects. | ||
<scene name='95/952716/Mras_and_pp1c/2'>TextToBeDisplayed</scene> | |||
=Overall Structure= | =Overall Structure= | ||
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<scene name='95/952717/Mras/2'>MRAS</scene> is a membrane-bound structure that aids the complex in localizing near other structures such as the RAS-RAF-MAPK complex in order to initiate downstream signaling. In its inactive state, MRAS is bound to GDP. When signaled by growth factors, the GDP is exchanged for GTP. The now <scene name='95/952718/Zoom_in_gtp/1'>GTP bound MRAS</scene> undergoes a conformational change of the <scene name='95/952716/Ras-switch-zoomed/1'>switch I and switch II regions</scene>. This conformational change activates the protein allowing it to bind with the SHOC2-PP1C complex. Without the conformational change when GDP is exchanged to GTP, the GDP-MRAS wouldn't be able to bind to SHOC2 because of steric clashing. In comparison to other RAS proteins, MRAS has a greater affinity for the SHOC2-PP1C complex. MRAS engages the SHOC2-PP1C complex and RAF on the same surface indicating that for RAF signaling two separate active MRASs are needed. Having two MRASs also help with the co-localization of PP1C to the NTpS region on RAF. | <scene name='95/952717/Mras/2'>MRAS</scene> is a membrane-bound structure that aids the complex in localizing near other structures such as the RAS-RAF-MAPK complex in order to initiate downstream signaling. In its inactive state, MRAS is bound to GDP. When signaled by growth factors, the GDP is exchanged for GTP. The now <scene name='95/952718/Zoom_in_gtp/1'>GTP bound MRAS</scene> undergoes a conformational change of the <scene name='95/952716/Ras-switch-zoomed/1'>switch I and switch II regions</scene>. This conformational change activates the protein allowing it to bind with the SHOC2-PP1C complex. Without the conformational change when GDP is exchanged to GTP, the GDP-MRAS wouldn't be able to bind to SHOC2 because of steric clashing. In comparison to other RAS proteins, MRAS has a greater affinity for the SHOC2-PP1C complex. MRAS engages the SHOC2-PP1C complex and RAF on the same surface indicating that for RAF signaling two separate active MRASs are needed. Having two MRASs also help with the co-localization of PP1C to the NTpS region on RAF. | ||
<scene name='95/952716/Newras-sw1-2/2'>TextToBeDisplayed</scene> | |||
= Key Ligand Interactions = | = Key Ligand Interactions = | ||
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== SHOC2 and MRAS == | == SHOC2 and MRAS == | ||
MRAS is initially bound to GDP causing it to be in its inactive state. This form cannot bind to the SHOC2-PP1C complex due to steric clashing (Figure 2). Once GDP is exchanged for GTP to activate the protein, <scene name='95/952716/ | MRAS is initially bound to GDP causing it to be in its inactive state. This form cannot bind to the SHOC2-PP1C complex due to steric clashing (Figure 2). Once GDP is exchanged for GTP to activate the protein, <scene name='95/952716/Scho2-mras-interactions/1'>conformational changes</scene> occur within the switch I and switch II regions to allow <scene name='95/952716/MRAS to interact with SHOC2/2'>SHOC2-MRAS(full-image)</scene>. These <scene name='95/952716/Scho2-mras-interactions/1'>interactions</scene> include hydrogen bonds and pi stacking. The primary hydrogen bonds are R288-Q71 and R177-E47. Pi staking occurs at R104-R83. | ||
<scene name='95/952716/Newmras-shco2/10'>TextToBeDisplayed</scene> | |||
[[Image:Switches.png|500 px|thumb|'''Figure 2:'''Steric clashing of Switch I and II of GDP bound MRAS, in green, with the surface of SHOC2, in magenta. GTP-bound MRAS, in white, shows no steric clashing with SHOC2s surface.</div></font>]] | [[Image:Switches.png|500 px|thumb|'''Figure 2:'''Steric clashing of Switch I and II of GDP bound MRAS, in green, with the surface of SHOC2, in magenta. GTP-bound MRAS, in white, shows no steric clashing with SHOC2s surface.</div></font>]] | ||
[[Image:Swtch1-2elementds.png |500 px| thumb| '''Figure 2:''' MRAS-GTP/SHOC2 PDB:7upI MRAS-GDP PDB:1x1r]] | |||
== PP1C and MRAS == | == PP1C and MRAS == | ||
The interactions between PP1C and MRAS are mediated by four main hydrogen bonds: R188-D48, M190-Q35, D197-H53, Q198-K36. It is unclear whether PP1C must bind to SHOC2 before MRAS binds or if PP1C and MRAS can bind to SHOC2 at the same time. | The interactions between PP1C and MRAS are mediated by four main hydrogen bonds: R188-D48, M190-Q35, D197-H53, Q198-K36. It is unclear whether PP1C must bind to SHOC2 before MRAS binds or if PP1C and MRAS can bind to SHOC2 at the same time. | ||
<scene name='95/952716/Mras_and_pp1c/2'>TextToBeDisplayed</scene> | |||
== Signaling Pathway == | == Signaling Pathway == | ||