Sandbox Reserved 1777: Difference between revisions
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==MRAS== | ==MRAS== | ||
<scene name='95/952705/Mras_structure/4'>MRAS</scene> is a monomeric GTPase and is anchored in the cell membrane by a C-terminal S-Farnesyl cysteine carboxylmethyl ester <Ref name='Zhou'> Zhou, Y., Prakash, P., Liang, H., et al. Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output. Cell, 168(1-2), 239–251.e16 doi: 10.1016/j.cell.2016.11.059. [https://doi.org/10.1016/j.cell.2016.11.059. DOI: 10.1016/j.cell.2016.11.059]. </Ref>. When MRAS binds GTP, it becomes active, which allows MRAS to bind the rest of the complex<ref name="Hauseman" />. MRAS is a subvariant of the RAS protein and therefore shares most of its regulatory and effector interactions<Ref name= 'Young'>Young, L., Rodriguez-Viciana, P. MRAS: A Close but Understudied Member of the RAS Family. Cold Spring Harbor Perspectives in Medicine (2018). doi: 10.1101/cshperspect.a033621. [https://perspectivesinmedicine.cshlp.org/content/8/12/a033621.full.pdf+html. DOI: 0.1101/cshperspect.a033621]. </Ref>. While other RAS variants bind in complex with SHOC2 and | <scene name='95/952705/Mras_structure/4'>MRAS</scene> is a monomeric GTPase and is anchored in the cell membrane by a C-terminal S-Farnesyl cysteine carboxylmethyl ester <Ref name='Zhou'> Zhou, Y., Prakash, P., Liang, H., et al. Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output. Cell, 168(1-2), 239–251.e16 doi: 10.1016/j.cell.2016.11.059. [https://doi.org/10.1016/j.cell.2016.11.059. DOI: 10.1016/j.cell.2016.11.059]. </Ref>. When MRAS binds GTP, it becomes active, which allows MRAS to bind the rest of the complex<ref name="Hauseman" />. MRAS is a subvariant of the RAS protein and therefore shares most of its regulatory and effector interactions<Ref name= 'Young'>Young, L., Rodriguez-Viciana, P. MRAS: A Close but Understudied Member of the RAS Family. Cold Spring Harbor Perspectives in Medicine (2018). doi: 10.1101/cshperspect.a033621. [https://perspectivesinmedicine.cshlp.org/content/8/12/a033621.full.pdf+html. DOI: 0.1101/cshperspect.a033621]. </Ref>. While other RAS variants bind in complex with SHOC2 and PP1C to allow it to have phosphatase activity, MRAS binds the tightest. | ||
===Switch I and II=== | ===Switch I and II=== | ||
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==Stabilizing Interactions in Ternary Complex== | ==Stabilizing Interactions in Ternary Complex== | ||
Once an initial signal to begin complex formation has been received, SHOC2 binds PP1C to form a binary complex. The SHOC2-PP1C complex then binds to the membrane bound MRAS. <scene name='95/ | Once an initial signal to begin complex formation has been received, SHOC2 binds PP1C to form a binary complex. The SHOC2-PP1C complex then binds to the membrane bound MRAS. <scene name='95/952705/Shoc2_pp1c_interaction/3'>PP1C binds</scene> with the ascending loops of the SHOC2 LRR regions, and is further engaged through the N-terminal region of SHOC2 which contains the <scene name='95/952706/Shoc2_rvxf/3'>RVxF motif</scene> <Ref name= 'Jajian'>Kwon, J., Jajian, B., Bian, Y. et al. Comprehensive structure-function evaluation of the SHOC2 holophosphatase reveals disease mechanisms and therapeutic opportunities. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022. [https://aacrjournals.org/cancerres/article/82/12_Supplement/LB029/699443. DOI: 10.1158/1538-7445.AM2022-LB029]. </Ref>. The initial forming of the complex begins with SHOC2-PP1C engagement, then is completed and stabilized by the GTP-loaded MRAS binding<Ref name="Jajian" />. <scene name='95/952705/Shoc2_mras_interaction/3'>MRAS binds to SHOC2</scene> exclusively through its concave LRRs<Ref name='Kwan'>Kwon, J.J., Hajian, B., Bian, Y. et al. Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex. Nature 609, 408–415 (2022).doi: 10.1038/s41586-022-04928-2. [https://doi.org/10.1038/s41586-022-04928-2. DOI:10.1038/s41586-022-04928-2] </Ref>, primarily by the descending loop and strands of LRR domains 2-10. Once associated with SHOC2, <scene name='95/952705/Mras_pp1c_interaction/3'>MRAS binds to PP1C</scene>. Binding to MRAS localizes the other two proteins to the RAS signaling regions of the membrane to begin cellular signaling<ref name="Kwan" />. | ||
==Active Site of PP1C== | ==Active Site of PP1C== | ||
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=Implications= | =Implications= | ||
[[Image:Noonan syndrome figure.jpg| | [[Image:Noonan syndrome figure.jpg|550px|right|thumb|<font size="2"><div style="text-align: center;">'''Figure 4'''. Common Symptoms of Noonan Syndrome. </div></font>]] | ||
The SHOC2-PP1C-MRAS complex's key role in the regulation of the MAPK-RAF pathway means that minor changes in its structure or function can have drastic biological consequences. Unregulated activation of the MAPK pathway is the cause of several human cancers due to unchecked cell division and proliferation<ref name="Kwan" />. Mutations that stabilize the interactions of the SMP complex enhance PP1C phosphatase activity <Ref name="Jajian" />, leading to increased RAF signaling and accelerated cell division. Most SHOC2 or PP1C mutations alter residues that are the direct contact points, stabilizing the interaction between the two proteins. Mutations to MRAS result in persistent binding of GTP, leading to consistent activation of the cell signaling pathway<ref name="Kwan" />. | The SHOC2-PP1C-MRAS complex's key role in the regulation of the MAPK-RAF pathway means that minor changes in its structure or function can have drastic biological consequences. Unregulated activation of the MAPK pathway is the cause of several human cancers due to unchecked cell division and proliferation<ref name="Kwan" />. Mutations that stabilize the interactions of the SMP complex enhance PP1C phosphatase activity <Ref name="Jajian" />, leading to increased RAF signaling and accelerated cell division. Most SHOC2 or PP1C mutations alter residues that are the direct contact points, stabilizing the interaction between the two proteins. Mutations to MRAS result in persistent binding of GTP, leading to consistent activation of the cell signaling pathway<ref name="Kwan" />. | ||
