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Introduction

Relevance

Cell Proliferation

Cancer

Structure of Subunits

SHOC2

PP1C

SHOC2 has a RVxF binding motif, that binds to the PP1C RVxF binding site. The N-terminal loop of SHOC2 interacts with the RVxF binding site of PP1C, showing 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 which allows 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. with or without binding to the SHOC2 complex.^[1].

MRAS

MRas localized the SHOC2 complex to the cell membrane by its C-terminus end. In its , there is a modified chain that allows it to bind to the cell membrane.^[1] 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.

Binding of the Subunits

Signaling Cascade

Autoinhibited Confirmation

Ras/Raf

Switch I and Switch II

Figure 1. Residues Interacting at SWI and SWII at subunits SHOC2 and PP1C.^[1].

Switch I (SWI) and Switch II (SWII) are located between the SHOC2 and MRas subunits. When GTP is hydrolyzed to GDP, Switch I and Switch II relax, in the relaxed state SHOC2 cannot bind to MRas. Two Residues from MRas interact with the gamma phosphate on GTP, changing the complex to the closed confirmation. When GTP is bound to , it triggers the assembly of the SHOC2 Complex. When SWI is in its open confirmation, PP1C cannot bind with MRas due to the steric clashes, but when GTP binds and SWI is in its closed confirmation, PP1C can bind without hinderance. In a mutated complex, other RAS proteins can replace MRas making cell proliferation more likely. SHOC2-PP1C-MRas may be used as a therapeutic target for cancer treatments through changing the confirmation of the .

Structure of Active Site

3-Metal Ion Catalysis

Hydrophobic Binding Site

Future Directions

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