Sandbox Reserved 1766: Difference between revisions

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=SHOC2-PP1C-MRAS=

<scene name='95/952694/Mras_switch_i/7'>TextToBeDisplayed</scene>

~~<scene name='95/952694/Pp1coverlay/3'>PP1C</scene>~~

~~<scene name='95/952694/Mrasswitchii/2'>MRAS at SWII</scene>~~

== Introduction ==

<scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) is a 3-subunit complex essential for cell proliferation and the survival of many cancers<ref name="Hauseman">PMID:35830882</ref> and RASopathies.<ref name="Kwon">PMID: 35831509</ref> The SMP holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for MAPK signaling.<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-Ras pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952694/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> PP1C is a phosphatase, and ~~this subunit~~ contains the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref>

<scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) is a 3-subunit complex essential for cell proliferation and the survival of many cancers<ref name="Hauseman">PMID:35830882</ref> and RASopathies.<ref name="Kwon">PMID: 35831509</ref> The SMP holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for MAPK signaling.<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-Ras pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952694/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1cintro/3'>The PP1C subunit</scene> is a phosphatase, and it contains the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref>

There are many regulatory mechanisms that serve as a lock on this RAS-MAPK pathway, decreasing the likelihood of unintentional pathway activation. One is a protein dimer called 14-3-3 that keeps inactive RAF localized to the cytoplasm. An N-terminal phosphorylated serine keeps RAF bound to this protein dimer, and when the SMP complex is assembled, the catalytic subunit, PP1C, removes the phosphate group from the serine, releasing RAF from the 14-3-3 dimer, and activating the RAS-MAPK cell proliferation pathway.

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There is a direct interaction between the RVXF motif of SHOC2 and the RVXF-binding pocket of PP1C.<ref name="Hauseman">PMID:35830882</ref>

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>.

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/4'>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>.

Sandbox Reserved 1766: Difference between revisions

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 =SHOC2-PP1C-MRAS=
 <StructureSection load='1stp' size='340' side='right' caption='SHOC2-MRAS-PP1C Holophosphatase Complex' scene='95/952694/Overall_image/2'>
+<scene name='95/952694/Mras_switch_i/7'>TextToBeDisplayed</scene>
-<scene name='95/952694/Mras_switch_i/6'>MRAS at SWI</scene>
-<scene name='95/952694/Pp1coverlay/3'>PP1C</scene>
-<scene name='95/952694/Mrasswitchii/2'>MRAS at SWII</scene>
 == Introduction ==
-<scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) is a 3-subunit complex essential for cell proliferation and the survival of many cancers<ref name="Hauseman">PMID:35830882</ref> and RASopathies.<ref name="Kwon">PMID: 35831509</ref> The SMP holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for MAPK signaling.<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-Ras pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952694/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> PP1C is a phosphatase, and this subunit contains the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref>
+<scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) is a 3-subunit complex essential for cell proliferation and the survival of many cancers<ref name="Hauseman">PMID:35830882</ref> and RASopathies.<ref name="Kwon">PMID: 35831509</ref> The SMP holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for MAPK signaling.<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-Ras pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952694/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1cintro/3'>The PP1C subunit</scene> is a phosphatase, and it contains the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref>
 There are many regulatory mechanisms that serve as a lock on this RAS-MAPK pathway, decreasing the likelihood of unintentional pathway activation. One is a protein dimer called 14-3-3 that keeps inactive RAF localized to the cytoplasm. An N-terminal phosphorylated serine keeps RAF bound to this protein dimer, and when the SMP complex is assembled, the catalytic subunit, PP1C, removes the phosphate group from the serine, releasing RAF from the 14-3-3 dimer, and activating the RAS-MAPK cell proliferation pathway.
@@ Line 35: / Line 31: @@
 There is a direct interaction between the RVXF motif of SHOC2 and the RVXF-binding pocket of PP1C.<ref name="Hauseman">PMID:35830882</ref>
-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>.
+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/4'>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>.