Sandbox Reserved 1766: Difference between revisions

 

<scene name='95/952694/Mras_switch_i/6'>MRAS at SWI</scene>

 

<scene name='95/952694/Overall_image/2'>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> When the subunits come together, the complex acts as a key regulator of the Receptor Tyrosine Kinase-Ras pathway and signaling cascade, by removing an inhibitory phosphorylation on the RAF family of proteins to increase MAPK (Mitogen-activated Protein Kinases) activity.<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>  

Within the SMP complex, each subunit uses an individual structure which correlates with its function. The three subunits are SHOC2, PP1C, and MRAS. The SHOC2 subunit uses a crescent shape to enhance substrate interactions and complex stability. It is essential for the binding of the SMP complex since it engages both PP1C and MRAS.<ref name="Liau">PMID: 35768504</ref> The protein phosphatase 1 catalytic (PP1C) subunit contains the catalytic active site of the complex.<ref name="Liau">PMID: 35768504</ref> PP1C is a phosphatase enzyme that dephosphorylates the N-terminal phosphoserine (NTpS) of RAF, but PP1C cannot dephosphorylate NTpS while isolated from the SMP complex.<ref name="Liau">PMID: 35768504</ref> Finally, the MRAS subunit controls the SMP complex formation based on GTP activation. 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>

The signaling cascade is kept from over-activating by being held in an auto-inhibited conformation. The SMP complex is responsible for removing this auto-inhibited conformation, allowing for Raf to bind to Ras. Mutations in any member of the SMP complex can lead to more frequent complex formation, ultimately leading to more, often uncontrolled, cell proliferation.<ref name="Kwon">PMID: 35831509</ref> SHOC2-PP1C-MRAS is being studied as a possible treatment target for many types of cancers.

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/2'>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>.

MRAS localized the SHOC2 complex to the cell membrane by its C-terminus end. In its <scene name='95/952694/Cell_membrane/2'>Cell Membrane Bound RAS Model</scene>, there is a modified chain that allows it to bind to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Normally, MRAS does not have the chain and it is only added after the modification. For MRas to bind, the SHOC-2 complex must be in the GTP bound state. When GDP is bound, there is a steric clash between Switch 1 and PP1C, so interaction with MRAS is not possible. Additionally, the surface of MRAS that is buried in the complex overlaps the surfaces used to engage RAF. It requires two MRAS interactions to activate a single RAF molecule.