Sandbox Reserved 1788: Difference between revisions

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OCA, Jaime Prilusky, Madeline Gilbert, Inaya Patel

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 == 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>]]
-<scene name='95/952718/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 RAF complex leading to further downstream signaling effects.
+<scene name='95/952718/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.
 == Overall Structure ==
 === SHOC2 ===
-<scene name='95/952717/Shoc2/1'>SHOC2</scene> is a crescent-shaped scaffold protein that is composed of 20 leucine-rich repeat domains that form a solenoid structure. The leucine-rich region forms a concave hydrophobic core which is necessary for binding with PP1C and MRAS.
+<scene name='95/952717/Shoc2/1'>SHOC2</scene> is a crescent-shaped scaffold protein that is composed of 20 leucine-rich repeat domains that form a solenoid structure. The leucine-rich region forms a concave hydrophobic core which is necessary for binding with PP1C and MRAS. SHOC2 is the crucial mediator for SHOC2-PP1C-MRAS complex formation.
 ===PP1C===
-<scene name='95/952717/Pp1c/1'>PP1C</scene> is a catalytic protein. After forming a ternary complex, the <scene name='95/952717/Pp1c_hydrophobic_patch/1'>hydrophobic active site</scene> on the protein interacts with Raf to act as a phosphatase and dephosphorylate Ser 259.
+<scene name='95/952717/Pp1c/1'>PP1C</scene> is a catalytic protein. After forming a ternary complex, the <scene name='95/952717/Pp1c_hydrophobic_patch/1'>hydrophobic active site</scene> on the protein interacts with Raf to act as a phosphatase and dephosphorylate Ser 259. PP1C's active site is adjacent to a hydrophobic patch. It's theorized that the hydrophobic patch binds to the C-terminal of N-terminal phosphoserine of RAF, the target for dephosphorylation. PP1C can act as a phosphatase in the absence of SHOC2 but PP1C lasks intrinsic substrate selectively. So SMP complex formation is necessary for PP1C specificity to RAF.
 === MRAS ===
-<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 more easily with the SHOC2-PP1C complex. In comparison to other RAS proteins, MRAS has a greater affinity for the SHOC2-PP1C complex.
+<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 more easily with the SHOC2-PP1C complex. 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.
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 === 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.
 == Signaling Pathway ==
+The SMP signaling pathway begins with the formation of the SMP complex. Initially, a ligand must bind to a  receptor tyrosine kinase. This signals SHOC2 to bind to PP1C forming a binary complex that then binds to the membrane bound MRAS. Some literature indicates that the three proteins bind at the same time but the order is largely unknown. Figure 2 shows the proteins binding one at a time. Once the SMP complex forms, its target is the N-terminal phosphoserine (NTpS) also known as S259. The serine is directly dephosphorylated by PP1C by SHOC2 and MRAS increase its specificity for S259.
+Mutations affecting SMP complex formation and stability have been shown to increase or decrease MAPK signaling. Increased stability of the complex increases MAPK signaling while decreased stability decreases signaling.
 [[Image:Signal_cascade_small.jpg|800 px|thumb|center|'''Figure 2:'''Signaling cascade is shown with SHOC2 in pink, PP1C in blue, and MRAs in white. ]]