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Introduction

Relevance

Cell Proliferation

Cancer

Structure of Subunits

SHOC2

PP1C

MRAS

Binding of the Subunits

Signaling Cascade

Autoinhibited Confirmation

The first step of the signaling cascade is the dephosphorylation of Raf at Ser259. In the , Raf interacts with a 14-3-3 dimer due to the phosphate group present on Ser259. This interaction with 14-3-3 restrics Raf to the cytoplasm and inhibits Raf from binding with Ras due to steric clash. When GTP binds to MRAS, this triggers the SMP complex to form. Once the complex is formed, PP1C is brought into close proximity of Ras, leading to the dephosphorylation of Ser259. Once dephosphorylated, Raf is in the , allowing for the interaction of Ras and Raf, and the initiation of the signaling cascade.

Ras/Raf

Switch I and Switch II

Structure of Active Site

3-Metal Ion Catalysis

The of the SHOC2-PP1C-MRAS complex resides in the PP1C subunit. 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. 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.

Hydrophobic Binding Site

PP1C has a adjacent to its active site. The majority of PP1C targets are able to bind through a specific motif that is recognized by the hydrophobic groove. In the Ras/Raf signaling cascade, the region of Raf that is C-terminal to the phosphate group binds to the hydrophobic groove, and the remaining residues bind to the hydrophobic region of SHOC2. This binding to SHOC2 is what allows the SMP complex to be more specific than PP1C on its own.

Future Directions

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