Sandbox Reserved 1777: Difference between revisions

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<scene name='95/952706/Shoc2_mras_interaction/2'>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. '''Add his sentence thing''' <scene name='95/952706/Shoc2_pp1c_interaction/5'>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" />. Once associated with SHOC2, <scene name='95/952706/Mras_pp1c_interaction/5'>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==

==Active Site of PP1C==

Once all the domains are bound, [https://en.wikipedia.org/wiki/Nucleoside_triphosphate NTpS] binds to PP1C in the active site. NTpS refers to the phosphorylated serine (residue 259) located at the N-terminus of RAF. Once NTpS is bound, PP1C catalyzes the dephosphorylation of serine 259. NTpS is dephosphorylated to prevent the active dimeric RAF from inactivating and changing into its monomeric structure. The <scene name='95/952705/Pp1c_active_site/4'>NTpS active site</scene> is surrounded by hydrophobic and acidic regions along with the C-terminus. These regions are located on the surface of PP1C, whereas the active site is placed further into the structure. It is thought that these regions help the ligand bind to the active site by making interactions that will lead NTpS into the protein. There is still some uncertainty as to how the substrate selectivity works, but these regions could play an essential role in it. Specifically, the pS from NTpS would bind to the hydrophobic region on PP1C<ref name="Liau">PMID:35768504</ref>.

Line 47:

[[Image:Screen Shot 2023-04-10 at 4.34.56 PM.jpeg|600px|thumb|<font size="2"><div style="text-align: center;">'''Figure 3'''. Schematic representation of RAF activation. PP1C removes an inhibitory phosphate group from RAF, which results in RAF activation and activation of the RAF/MAPK signaling cascade. </div></font>]]

Once the SMP complex comes together, it plays a key role in regulating the activation of the RAF/MAPK pathway. PP1C, enhanced through interactions with SHOC2 and MRAS, removes a phosphate group from serine residue 259 (also known as NTpS) of RAF. The removal of the phosphate group triggers activation of RAF, a serine/threonine kinase, which leads to the phosphorylation and activation of MAPK. This causes the activation of downstream proteins ERK1 and ERK2, which are responsible for activating nuclear transcription factors such as Elk-1, c-Ets1, C-Ets2, and MNK1, which result in the transcription of genes that code for proteins which promote cell proliferation and differentiation. <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signaling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>.

Once the SMP complex comes together, it plays a key role in regulating the activation of the RAF/MAPK pathway. PP1C, enhanced through interactions with SHOC2 and MRAS, removes a phosphate group from serine residue 259 (also known as NTpS) of RAF. The removal of the phosphate group triggers activation of RAF, a serine/threonine kinase, which leads to the phosphorylation and activation of MAPK. This causes the activation of downstream proteins ERK1 and ERK2, which are responsible for activating nuclear transcription factors such as Elk-1, c-Ets1, c-Ets2, and MNK1, which result in the transcription of genes that code for proteins which promote cell proliferation and differentiation. <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signaling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>.

=Implications=

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@@ Line 37: / Line 37: @@
 <scene name='95/952706/Shoc2_mras_interaction/2'>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. '''Add his sentence thing''' <scene name='95/952706/Shoc2_pp1c_interaction/5'>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" />. Once associated with SHOC2, <scene name='95/952706/Mras_pp1c_interaction/5'>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==
+==Active Site of PP1C==
 Once all the domains are bound, [https://en.wikipedia.org/wiki/Nucleoside_triphosphate NTpS] binds to PP1C in the active site. NTpS refers to the phosphorylated serine (residue 259) located at the N-terminus of RAF. Once NTpS is bound, PP1C catalyzes the dephosphorylation of serine 259. NTpS is dephosphorylated to prevent the active dimeric RAF from inactivating and changing into its monomeric structure. The <scene name='95/952705/Pp1c_active_site/4'>NTpS active site</scene> is surrounded by hydrophobic and acidic regions along with the C-terminus. These regions are located on the surface of PP1C, whereas the active site is placed further into the structure. It is thought that these regions help the ligand bind to the active site by making interactions that will lead NTpS into the protein. There is still some uncertainty as to how the substrate selectivity works, but these regions could play an essential role in it. Specifically, the pS from NTpS would bind to the hydrophobic region on PP1C<ref name="Liau">PMID:35768504</ref>.
@@ Line 47: / Line 47: @@
 [[Image:Screen Shot 2023-04-10 at 4.34.56 PM.jpeg|600px|thumb|<font size="2"><div style="text-align: center;">'''Figure 3'''. Schematic representation of RAF activation. PP1C removes an inhibitory phosphate group from RAF, which results in RAF activation and activation of the RAF/MAPK signaling cascade. </div></font>]]
-Once the SMP complex comes together, it plays a key role in regulating the activation of the RAF/MAPK pathway. PP1C, enhanced through interactions with SHOC2 and MRAS, removes a phosphate group from serine residue 259 (also known as NTpS) of RAF. The removal of the phosphate group triggers activation of RAF, a serine/threonine kinase, which leads to the phosphorylation and activation of MAPK. This causes the activation of downstream proteins ERK1 and ERK2, which are responsible for activating nuclear transcription factors such as Elk-1, c-Ets1, C-Ets2, and MNK1, which result in the transcription of genes that code for proteins which promote cell proliferation and differentiation.  <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signaling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>.
+Once the SMP complex comes together, it plays a key role in regulating the activation of the RAF/MAPK pathway. PP1C, enhanced through interactions with SHOC2 and MRAS, removes a phosphate group from serine residue 259 (also known as NTpS) of RAF. The removal of the phosphate group triggers activation of RAF, a serine/threonine kinase, which leads to the phosphorylation and activation of MAPK. This causes the activation of downstream proteins ERK1 and ERK2, which are responsible for activating nuclear transcription factors such as Elk-1, c-Ets1, c-Ets2, and MNK1, which result in the transcription of genes that code for proteins which promote cell proliferation and differentiation.  <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signaling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>.
 =Implications=