Sandbox Reserved 1790: Difference between revisions

<scene name='95/952716/Membrane/1'>MRAS</scene> is a monomeric GTPase. MRAS is membrane-bound due to post-translational lipidation which allows the protein to interact with the inner membrane leaflet. <ref name="Seabra">PMID:9607139</ref> MRAS localizes the SMP complex near RAF and other components of downstream signaling. The region of MRAS not directly bound to the membrane binds SHOC2 and PP1C to orient the complex such that PP1C’s active site faces the serine that will get dephosphorylated on RAF. MRAS also controls SMP complex formation in connection with extracellular signaling based on its dualistic switching between its inactive and active state. In its inactive state, MRAS is bound to GDP. When signaled by growth factors, the GDP is exchanged for GTP when a ligand binds to the RTK <ref name="Hauseman" />. The now <scene name='95/952718/Zoom_in_gtp/2'>GTP bound MRAS</scene> undergoes a conformational change of the  <scene name='95/952716/Newras-sw1-2/2'>switch I and II regions</scene>. These regions are the major binding sites with SHOC2. This conformational change activates MRAS allowing it to bind with the SHOC2-PP1C complex. In its inactive GDP-bound state, MRAS is sterically occluded from binding SHOC2. For example, R83 of GDP-bound MRAS directly clashes with SHOC2 as shown in figure 2. In comparison to other RAS proteins such as H/K/NRAS, MRAS has a greater affinity for the SHOC2-PP1C complex<ref name="Kubicek">Kubicek M, Pacher M, Abraham D, Podar K, Eulitz M, Baccarini M. Dephosphorylation of Ser-259 regulates Raf-1 membrane association. J Biol Chem. 2002 Mar 8;277(10):7913-9. [http://10.1074/jbc.M108733200 doi: 10.1074/jbc.M108733200.]</ref>. This indicates that the specific structure of MRAS is necessary for SMP function. While MRAS engages the SHOC2-PP1C complex to bring the complex to the membrane, an additional membrane-bound RAS binds RAF nearby. This binding is also stimulated by ligand binding to the RTK. This indicates that for full RAF activation and continuous signaling of Raf, two separate active RAS proteins are needed. Having two MRASs also help with the co-localization of PP1C to the NTpS region on RAF. To inactivate Raf signaling, MRAS uses its intrinsic GTPase to remove the activating gamma-phosphate on GTP. In the GDP-bound state, switch I and II move to the position shown in green in Figure 2. This inactivates SHOC2 binding due to steric clashing which causes the SMP structure to dissociate.