Sandbox Reserved 1790: Difference between revisions
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===SHOC2 and PP1C interactions=== | ===SHOC2 and PP1C interactions=== | ||
<scene name='95/952717/Shoc2_and_pp1c/1'>PP1C binds to SHOC2</scene> on its leucine rich region(LRR). Between LRR2 and LRR5 and between LRR7 and LRR11. Mutations between SHOC2 and PP1C to the LRR were shown to completely inhibit the binding of PP1C. Five main <scene name='95/952716/Shoc2_and_pp1c/3'>hydrogen and ionic bonds</scene> are made between PP1C and SHOC2 respectively: E56-R182, E167-R203, E54-K180, R187-H178, R188-E155 <ref name="Kwon">PMID:35831509</ref>. Reflecting this ionic character, the binding regions are contained within extensive acidic and basic patches on <scene name='95/952718/Acid_base_pp1c/ | <scene name='95/952717/Shoc2_and_pp1c/1'>PP1C binds to SHOC2</scene> on its leucine rich region(LRR). Between LRR2 and LRR5 and between LRR7 and LRR11. Mutations between SHOC2 and PP1C to the LRR were shown to completely inhibit the binding of PP1C. Five main <scene name='95/952716/Shoc2_and_pp1c/3'>hydrogen and ionic bonds</scene> are made between PP1C and SHOC2 respectively: E56-R182, E167-R203, E54-K180, R187-H178, R188-E155 <ref name="Kwon">PMID:35831509</ref>. Reflecting this ionic character, the binding regions are contained within extensive acidic and basic patches on <scene name='95/952718/Acid_base_pp1c/2'>PP1C</scene> and <scene name='95/952718/Acid_base_shoc2/2'>SHOC2</scene>. The negative acidic patches of PP1C interact with the positive basic patches of SHOC2 and vice versa to form a <scene name='95/952718/Acid_base_shoc2pp1c/1'>binary complex</scene>. These interactions do not result in significant conformational changes to PP1C in comparison to other protein interactions that can be made with PP1C <ref name="Kwon">PMID:35831509</ref>. | ||
==MRAS== | ==MRAS== | ||
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=Signaling Pathway= | =Signaling Pathway= | ||
The SMP signaling pathway begins with the formation of the SMP complex. Initially, a ligand must bind to a receptor tyrosine kinase. This signals SHOC2 to bind to PP1C forming a binary complex that then binds to the membrane-bound MRAS. There is some discrepancy about when the different proteins of the SMP complex come together <ref name="Liau">PMID:35768504</ref>, however, we chose to depict the order as shown in Figure 3 for more clear visualization. Some experiments indicate that the three proteins bind at the same time but the order is largely unknown. Once the SMP complex forms, its intracellular target is a key inactivation phosphorylation (Ser259) on MAPK RAF-1. The serine is directly dephosphorylated by PP1C, while SHOC2 and MRAS increase PP1C’s specificity for S259 on RAF <ref name="Liau" />. When analyzing the surface structure of SHOC1-PP1C-MRAS, there was a hydrophobic groove on the SHOC2 terminus and another hydrophobic groove near the active site on PP1C <ref name="Liau" />. This region is crucial in making PP1C specific to RAF because the NTpS region that is right next to the phosphoserine on RAF is able to bind to the hydrophobic patch on both SHOC2 and PP1C <ref name="Liau" />. | The SMP signaling pathway begins with the formation of the SMP complex. Initially, a ligand must bind to a receptor tyrosine kinase. This signals SHOC2 to bind to PP1C forming a binary complex that then binds to the membrane-bound MRAS. There is some discrepancy about when the different proteins of the SMP complex come together <ref name="Liau">PMID:35768504</ref>, however, we chose to depict the order as shown in Figure 3 for more clear visualization. Some experiments indicate that the three proteins bind at the same time but the order is largely unknown. Once the SMP complex forms, its intracellular target is a key inactivation phosphorylation (Ser259) on MAPK RAF-1. The serine is directly dephosphorylated by PP1C, while SHOC2 and MRAS increase PP1C’s specificity for S259 on RAF <ref name="Liau" />. When analyzing the surface structure of SHOC1-PP1C-MRAS, there was a hydrophobic groove on the SHOC2 terminus and another hydrophobic groove near the active site on PP1C <ref name="Liau" />. This region is crucial in making PP1C specific to RAF because the NTpS region that is right next to the phosphoserine on RAF is able to bind to the hydrophobic patch on both SHOC2 and PP1C <ref name="Liau" />. | ||
Mutations affecting SMP complex formation and stability can increase or decrease MAPK signaling, where increased stability of the complex increases MAPK signaling, decreased stability decreases signaling <ref name="Liau" />. There are a set of mutations that can happen on the SMP complex as a whole that can cause [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422. Noonan syndrome], a rasopathy disorder <ref name=" | Mutations affecting SMP complex formation and stability can increase or decrease MAPK signaling, where increased stability of the complex increases MAPK signaling, decreased stability decreases signaling <ref name="Liau" />. There are a set of mutations that can happen on the SMP complex as a whole that can cause [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422. Noonan syndrome], a rasopathy disorder <ref name="Hauseman" />. On SHOC2, the following mutations S2G, C260Y, and P510L caused differences in the complex formation with PP1C. On PP1C, the mutation P50R resulted in stronger ionic interactions with residues on SHOC2, causing a more stabilized complex. On MRAS, mutations G23V and T681I, increased the proportion of MRAS that is GTP bound, which results in increased affinity in the SMP complex overall <ref name="Liau" />. If these mutations happen all at once, or just one or two at a time, it can still significantly alter the functionality of the SMP complex. This can lead to diseases like Noonan syndrome, which is where there are developmental and growth issues and can even lead to cancers <ref name="Rauen" />. | ||
===Future Studies=== | ===Future Studies=== | ||
With this understood knowledge about how the SMP is able to contribute to an increase or decrease of MAPK pathways, there can be further research done to develop treatments for various cancers and rasopathies <ref name="Liau" />. Research can be done to develop [https://www.sciencedirect.com/topics/earth-and-planetary-sciences/enzyme-inhibitor. inhibitors] that can alter the affinity of the SMP complex in order to regulate MAPK signaling pathways. This can help treat diseases that are caused by unregulated cell proliferation <ref name="Lavoie">. Another possible point of inhibition is the growth factor that signals SHOC2-PP1C and Raf to the cell membrane | With this understood knowledge about how the SMP is able to contribute to an increase or decrease of MAPK pathways, there can be further research done to develop treatments for various cancers and rasopathies <ref name="Liau" />. Research can be done to develop [https://www.sciencedirect.com/topics/earth-and-planetary-sciences/enzyme-inhibitor. inhibitors] that can alter the affinity of the SMP complex in order to regulate MAPK signaling pathways. This can help treat diseases that are caused by unregulated cell proliferation<ref name="Lavoie" />. Another possible point of inhibition is the growth factor that signals SHOC2-PP1C and Raf to the cell membrane <ref name="Liau" />. | ||
[[Image:Complex.png|800 px|thumb|center|'''Figure 3:'''Signaling cascade is shown with SHOC2 (magenta), PP1C (blue), and MRAS (white). SHOC2 binds to PP1C then to MRAS at the cell membrane. The SMP complex is now oriented near the membrane-bound RAF complex (green) allowing PP1C to phosphorylate RAF at serine 259.]] | [[Image:Complex.png|800 px|thumb|center|'''Figure 3:'''Signaling cascade is shown with SHOC2 (magenta), PP1C (blue), and MRAS (white). SHOC2 binds to PP1C then to MRAS at the cell membrane. The SMP complex is now oriented near the membrane-bound RAF complex (green) allowing PP1C to phosphorylate RAF at serine 259.]] | ||