Sandbox Reserved 1766: Difference between revisions

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PP1C activity is regulated by PP1C-binding regulatory proteins.<ref name="Hauseman">PMID:35830882</ref> The regulatory proteins may bind to small motifs in PP1C, like RVXF.<ref name="Liau">PMID: 35768504</ref> The RVXF motif is located in PP1C through the N-terminal disordered region.<ref name="Kwon">PMID: 35831509</ref>  
PP1C activity is regulated by PP1C-binding regulatory proteins.<ref name="Hauseman">PMID:35830882</ref> The regulatory proteins may bind to small motifs in PP1C, like RVXF.<ref name="Liau">PMID: 35768504</ref> The RVXF motif is located in PP1C through the N-terminal disordered region.<ref name="Kwon">PMID: 35831509</ref>  


**FROM THE INITIAL FIRST DRAFT: 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>.
**FROM THE INITIAL FIRST DRAFT: 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>
 
 


=== MRAS ===
=== MRAS ===
MRAS localized the SHOC2 complex to the cell membrane by its C-terminus end. In its <scene name='95/952694/Cell_membrane/3'>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.  
 
 
Ras proteins are GTP dependent switches that are associated with the plasma membrane.<ref name="Liau">PMID: 35768504</ref> Ras proteins often regulate cycles during signal transduction. MRAS, one of the subunits in the SMP complex, is a RAS protein specific to SHOC2 and the SMP complex. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower Kd (dissociation constant), thus has the strongest connection.<ref name="Liau">PMID: 35768504</ref> The interface between SHOC2 and MRAS consists of two switches, Switch I and Switch II.<ref name="Liau">PMID: 35768504</ref> The switch regions were the only regions in MRAS to conformationally change, depending on the state of GTP.<ref name="Liau">PMID: 35768504</ref>
 
The formation of the SMP complex is stabilized and driven by the MRAS GTP-bound active state.<ref name="Hauseman">PMID:35830882</ref><ref name="Kwon">PMID: 35831509</ref> The tertiary structure formation is GTP dependent on multiple RAS forms.<ref name="Hauseman">PMID:35830882</ref> When GTP is bound to MRAS, the SMP complex forms and MRAS is in the active form. When GDP is bound to MRAS, the SMP complex does not form and MRAS is in the inactive form.<ref name="Liau">PMID: 35768504</ref> In order for MRAS to bind to SHOC2, MRAS must be in the active GTP bound state. When the inactive GDP is bound to MRAS, steric clashes between Switch 1 on MRAS and PP1C prevent SHOC2 binding and the SMP complex formation.<ref name="Liau">PMID: 35768504</ref>
 
Additionally, the surface of MRAS that is buried in the complex overlaps the surfaces used to engage RAF, requiring two separate MRAS proteins to activate a single RAF molecule, one in the SMP complex and one to dephosphorylated Raf to activate the MAPK signaling cascade. The SMP complex is localized to the cell membrane or other RAS isoforms by the palmitoylated, C-terminus end of MRAS.<ref name="Hauseman">PMID:35830882</ref> In its <scene name='95/952694/Cell_membrane/3'>cell membrane bound Ras model</scene>, Ras has an extended, palmitoylated C-terminal helix which allows it to bind to the cell membrane.<ref name="Liau">PMID: 35768504</ref>
 
 
 




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