Sandbox Reserved 1767: Difference between revisions

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==RAS==

RAS proteins are GTP-dependent intracellular switches that are anchored to the plasma membrane. .<ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation. <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower Kd (dissociation constant).<ref name="Liau">PMID: 35768504</ref> There are no known membrane interacting regions on SHOC2 and PP1C, meaning the hydrophobic fatty acid tail on MRAS is responsible for recruiting the complex to the cell membrane .<ref name="Hauseman">PMID:35830882</ref>.

A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and Raf. In figure 1, MRAS is shown in green, with the SHOC2 binding site colored cyan, the PP1C binding site colored green, and the RAF binding site shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF. The ability of scene name='95/952694/Cell_membrane/3'>MRAS-GTP to cluster at the cell membrane</scene> is a crucial capability for this protein complex. The presence of this scene name='95/952694/Cell_membrane/3'>palmitoyl tail on RAS </scene>is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane, allowing only for 2D movement and increasing local concentrations of the players needed in this signaling pathway. .<ref name="Hauseman">PMID:35830882</ref>

The Ras-Raf signaling cascade will be inhibited without the dephosphorylation of Raf at Ser259. There is a <scene name='95/952695/14-3-3/1'>14-3-3</scene> dimer present in the cytoplasm that interacts with Raf through hydrogen bonds between R129 of 14-3-3 and Ser259 of Raf when Ser259 is phosphorylated. This interaction causes an <scene name='95/952695/Autoinhibited_confirmation/7'>autoinhibited confirmation</scene> as 14-3-3 restricts Raf to the cytoplasm and sterically inhibits Raf from binding with activated Ras. This interaction is crucial in regulating cell proliferation, as it prevents cell growth in the absence of a signal. Extracellular growth factors trigger GTP to bind to MRAS, which triggers SMP formation. Upon SMP complex formation, PP1C is brought into close proximity of Ras, leading to the dephosphorylation of Ser259 of Raf by the active site of PP1C. Once dephosphorylated, Raf is in the <scene name='95/952695/Non-inhibited_confirmation/9'>active confirmation</scene>, allowing for the interaction of Ras and Raf, and the initiation of the signaling cascade.<ref name="Young">PMID: 30348783</ref>

MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP. <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS lead to consistent GTP-loading, causing an increase in the formation of the SMP complex and there is consistent activation of the cell-proliferation pathway in the absence of external growth factors.

===Auto-inhibition===

The Ras-Raf signaling cascade will be inhibited without the dephosphorylation of Raf at Ser259. There is a <scene name='95/952695/14-3-3/1'>14-3-3</scene> dimer present in the cytoplasm that interacts with Raf through hydrogen bonds between R129 of 14-3-3 and Ser259 of Raf when Ser259 is phosphorylated. This interaction causes an <scene name='95/952695/Autoinhibited_confirmation/7'>autoinhibited confirmation</scene> as 14-3-3 restricts Raf to the cytoplasm and sterically inhibits Raf from binding with activated Ras. This interaction is crucial in regulating cell proliferation, as it prevents cell growth in the absence of a signal. Extracellular growth factors trigger GTP to bind to MRAS, which triggers SMP formation. Upon SMP complex formation, PP1C is brought into close proximity of Ras, leading to the dephosphorylation of Ser259 of Raf by the active site of PP1C. Once dephosphorylated, Raf is in the <scene name='95/952695/Non-inhibited_confirmation/9'>active confirmation</scene>, allowing for the interaction of Ras and Raf, and the initiation of the signaling cascade.<ref name="Young">PMID: 30348783</ref>

=== Switch I and Switch II ===

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@@ Line 35: / Line 35: @@
 ==RAS==
+RAS proteins are GTP-dependent intracellular switches that are anchored to the plasma membrane. .<ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation. <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower Kd (dissociation constant).<ref name="Liau">PMID: 35768504</ref> There are no known membrane interacting regions on SHOC2 and PP1C, meaning the hydrophobic fatty acid tail on MRAS is responsible for recruiting the complex to the cell membrane .<ref name="Hauseman">PMID:35830882</ref>.
+A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and Raf. In figure 1, MRAS is shown in green, with the SHOC2 binding site colored cyan, the PP1C binding site colored green, and the RAF binding site shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF. The ability of scene name='95/952694/Cell_membrane/3'>MRAS-GTP to cluster at the cell membrane</scene> is a crucial capability for this protein complex. The presence of this scene name='95/952694/Cell_membrane/3'>palmitoyl tail on RAS </scene>is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane, allowing only for 2D movement and increasing local concentrations of the players needed in this signaling pathway. .<ref name="Hauseman">PMID:35830882</ref>
-The Ras-Raf signaling cascade will be inhibited without the dephosphorylation of Raf at Ser259. There is a <scene name='95/952695/14-3-3/1'>14-3-3</scene> dimer present in the cytoplasm that interacts with Raf through hydrogen bonds between R129 of 14-3-3 and Ser259 of Raf when Ser259 is phosphorylated. This interaction causes an <scene name='95/952695/Autoinhibited_confirmation/7'>autoinhibited confirmation</scene> as 14-3-3 restricts Raf to the cytoplasm and sterically inhibits Raf from binding with activated Ras. This interaction is crucial in regulating cell proliferation, as it prevents cell growth in the absence of a signal. Extracellular growth factors trigger GTP to bind to MRAS, which triggers SMP formation. Upon SMP complex formation, PP1C is brought into close proximity of Ras, leading to the dephosphorylation of Ser259 of Raf by the active site of PP1C. Once dephosphorylated, Raf is in the <scene name='95/952695/Non-inhibited_confirmation/9'>active confirmation</scene>, allowing for the interaction of Ras and Raf, and the initiation of the signaling cascade.<ref name="Young">PMID: 30348783</ref>
+MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP. <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS lead to consistent GTP-loading, causing an increase in the formation of the SMP complex and there is consistent activation of the cell-proliferation pathway in the absence of external growth factors.
+===Auto-inhibition===
+The Ras-Raf signaling cascade will be inhibited without the dephosphorylation of Raf at Ser259. There is a <scene name='95/952695/14-3-3/1'>14-3-3</scene> dimer present in the cytoplasm that interacts with Raf through hydrogen bonds between R129 of 14-3-3 and Ser259 of Raf when Ser259 is phosphorylated. This interaction causes an <scene name='95/952695/Autoinhibited_confirmation/7'>autoinhibited confirmation</scene> as 14-3-3 restricts Raf to the cytoplasm and sterically inhibits Raf from binding with activated Ras. This interaction is crucial in regulating cell proliferation, as it prevents cell growth in the absence of a signal. Extracellular growth factors trigger GTP to bind to MRAS, which triggers SMP formation. Upon SMP complex formation, PP1C is brought into close proximity of Ras, leading to the dephosphorylation of Ser259 of Raf by the active site of PP1C. Once dephosphorylated, Raf is in the <scene name='95/952695/Non-inhibited_confirmation/9'>active confirmation</scene>, allowing for the interaction of Ras and Raf, and the initiation of the signaling cascade.<ref name="Young">PMID: 30348783</ref>
 === Switch I and Switch II ===