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Introduction

SHOC2-MRAS-PP1C, also known as the SMP complex, is a 3-subunit complex essential for cell proliferation and the survival of many cancers and RASopathies. When the subunits comes together, it plays a key role in the activation of the Ras-Raf pathway and signaling cascade. Each subunit of the complex has an individual structure which correlates with its function. SHOC2 has a crescent shape in order to enhance substrate interactions and interactions between the subunits, while PP1C holds the catalytic active site and, the C-terminus of MRAS localizes the complex to the cell membrane. Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, leading to cancer and developmental disorders called RASopathies. 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 the subunits can lead to more frequent complex formation, ultimately leading to more cell proliferation. SHOC2-PP1C-MRAS is being studied as a possible treatment target for many types of cancers.

In all images and animations, SHOC2 will be shown as cyan blue, MRAS as lime, and PP1C as violet. Other important components involved in the function of the SMP complex include the 14-3-3 dimer and Raf, which will be shown in salmon and slate-blue, respectively.

Relevance

Cell Proliferation

The Ras-Raf signaling cascade as a whole is fundamental for cell growth and survival. A membrane bound GTPase that is part of the Ras family, in this particular case, MRAS, is activated by extra-cellular growth factor proteins. When MRAS is GTP-bound rather than GDP-bound,

Cancer and RASopathies

- mutations are at the protein-protein interaction surfaces, leads to more stability of the complex and increased interaction energy of SHOC2 with PP1c and/or MRAS. - other RAS proteins can bind in a mutated complex rather than just MRAS - SHOC2 is necessary in all cases

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

- knockdown of SHOC2

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