Sandbox Reserved 1767: Difference between revisions

SHOC2-PP1C-MRAS is a regulator of a cell proliferation pathway. Mutations in cell proliferation pathways are responsible for 25% of all cancers 1. If this cell proliferation pathway goes unmediated, rapid cell growth and division will occur; the leading cause of cancers is mutations in this pathway. <ref name="Lavoie">PMID: 35970881</ref> [https://www.nature.com/articles/d41586-022-02189-7 Mechanistic Overview and Signaling Cascade ] shows the pathway SHOC2-PP1C-MRAS is part of. It is a receptor tyrosine kinase pathway.<ref name="Kwon">PMID: 35831509</ref>  When MRAS is bound to GDP, the complex is not assembled. SHOC2, PP1C, and MRAS all exist as separate monomers. The Raf domain contains a kinase domain (KD), Ras binding domain (RBD), a C-terminal phosphoserine (CTpS), a N-terminal phosphorylated serine (NTpS), and a 14-3-3 protein dimer, restricting RAF to the cytoplasm. In the activated pathway, MRAS is bound to GTP, and the SMP complex is assembled. PP1C is now in contact with the NTpS, allowing it to become dephosphorylated. <ref name="Lavoie">PMID: 35970881</ref> This dephosphorylation causes the dimerization of two Raf proteins via their kinase domains as well as a conformational change. This conformation change causes the phosphorylation of other residues. Eventually, this leads to the unbinding of GDP from MRAS and the binding of GTP to MRAS, causing a shift from the <scene name='95/952693/Swi_open_conformation/6'>open conformation</scene> to <scene name='95/952693/Switch_i_gtp_bound/11'>closed conformation of SWI.</scene> The Switch I region is made up of residues 42-48 of the MRAS domain.<ref name="Kwon">PMID: 35831509</ref> These residues are crucial for the binding of MRAS, SHOC2, and PP1C. When GDP is bound to the MRAS domain, it is in the <scene name='95/952693/Swi_open_conformation/6'>open conformation.</scene> Since the gamma P is not bound to GDP, there are no hydrogen bond interactions with the oxygens of the phosphate group- hence the open conformation. When GTP is bound to MRAS, it is in the <scene name='95/952693/Switch_i_gtp_bound/11'>closed conformation.</scene> The closed conformation allows for the binding of SHOC2 and PP1C. The open conformation of MRAS sterically clashes with the binding site of SHOC2, which is why the complex is not assembled when GDP is bound. <ref name="Kwon">PMID: 35831509</ref>.

The <scene name='95/952695/Pp1c_active_site/4'>catalytic active site </scene>of the SHOC2-PP1C-MRAS complex resides in the PP1C subunit.<ref name="Hurley">PMID: 17636256</ref> The role of PP1C is to dephosphorylate SER259 of Raf so that the signaling cascade can start. The active site is unchanged upon the binding of the complex, however, SHOC2 and MRAS aid in the specificity of the enzymatic activity as PP1C is able to dephosphorylate many different targets on its own, with almost 100 PP1C targets found.<ref name="Young">PMID: 30348783</ref> The full mechanism for the catalytic activity is unknown, however, there are 3 metal ions present (2-Mg2+ and 1-Cl-) to stabilize the waters present in the active site. Additionally, the substrate binds through hydrogen bonds with the main chain and side chain atoms of the catalytic residues. Mutations in the active site lead to increased activity, causing the Ras/Raf signaling cascade to be triggered more frequently.<ref name="Hurley">PMID: 17636256</ref>