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==RAS== | ==RAS== | ||
RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane | RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane. This allows only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <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 <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''', {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2 binding site}} colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|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 <ref name="Lavoie">PMID: 35970881</ref>. 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 <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</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. | A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''', {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2 binding site}} colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|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 <ref name="Lavoie">PMID: 35970881</ref>. 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 <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</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. | ||