Sandbox Reserved 1777: Difference between revisions

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A key feature in allowing MRAS to be in its active versus inactive state is the switches in MRAS. When MRAS is active, GTP is bound and the switches allow MRAS to be bound with PP1C. When MRAS is inactive, GDP is bound and the switches do not allow MRAS to bind to PP1C. The switches determine whether MRAS can bind to SHOC2-PP1C. The switches have to go through a conformational change to allow binding of SHOC2-PP1C to MRAS. The conformational change is needed because without it SHOC2-PP1C could bind to MRAS when MRAS is still inactive. This process would cause the SHOC2-PP1C-MRAS pathway to constantly be running. The switches and GDP/GTP help regulate this process.

This conformational change is caused by GTP replacing GDP. When GTP is bound, MRAS shifts and binds with the previously associated SHOC2-PP1C complex. When GDP is bound, <scene name='95/952705/Switch_i_and_ii_with_gdp/8'>switch II</scene> in MRAS is moved outward, which causes a steric clash with SHOC2 <scene name='95/952705/Gdp_with_mras_and_shoc2/2'>(SHOC2 with Closed Switches)</scene>. When GTP is bound, <scene name='95/952705/Switch_i_and_ii_with_gtp/5'>~~Switch~~ II</scene> in MRAS can form various hydrogen bonding, pi stacking and hydrophobic interactions with SHOC2<Ref name='Bonsor'>Daniel A. Bonsor, Patrick Alexander, Kelly Snead, Nicole Hartig, Matthew Drew, Simon Messing, Lorenzo I. Finci, Dwight V. Nissley, Frank McCormick, Dominic Esposito, Pablo Rodrigiguez-Viciana, Andrew G. Stephen, Dhirendra K. Simanshu. Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome. bioRxiv. 2022.05.10.491335. doi: 10.1101/2022.05.10.491335. [https://doi.org/10.1101/2022.05.10.491335. DOI:10.1101/2022.05.10.491335]. </Ref>. When MRAS is bound to SHOC2-PP1C, switch I has an important role in making interactions with PP1C<scene name='95/952705/Switch_i_and_ii_with_gtp/7'>(SHOC2 with Open Switches)</scene>. Though it is minute there is a change of the positioning of switch II when GDP vs GTP is bound.

This conformational change is caused by GTP replacing GDP. When GTP is bound, MRAS shifts and binds with the previously associated SHOC2-PP1C complex. When GDP is bound, <scene name='95/952705/Switch_i_and_ii_with_gdp/8'>switch II</scene> in MRAS is moved outward, which causes a steric clash with SHOC2 <scene name='95/952705/Gdp_with_mras_and_shoc2/2'>(SHOC2 with Closed Switches)</scene>. When GTP is bound, <scene name='95/952705/Switch_i_and_ii_with_gtp/5'>switch II</scene> in MRAS can form various hydrogen bonding, pi stacking and hydrophobic interactions with SHOC2<Ref name='Bonsor'>Daniel A. Bonsor, Patrick Alexander, Kelly Snead, Nicole Hartig, Matthew Drew, Simon Messing, Lorenzo I. Finci, Dwight V. Nissley, Frank McCormick, Dominic Esposito, Pablo Rodrigiguez-Viciana, Andrew G. Stephen, Dhirendra K. Simanshu. Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome. bioRxiv. 2022.05.10.491335. doi: 10.1101/2022.05.10.491335. [https://doi.org/10.1101/2022.05.10.491335. DOI:10.1101/2022.05.10.491335]. </Ref>. When MRAS is bound to SHOC2-PP1C, switch I has an important role in making interactions with PP1C<scene name='95/952705/Switch_i_and_ii_with_gtp/7'>(SHOC2 with Open Switches)</scene>. Though it is minute there is a change of the positioning of switch II when GDP vs GTP is bound.

==Stabilizing Interactions in Ternary Complex==

Sandbox Reserved 1777: Difference between revisions

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 A key feature in allowing MRAS to be in its active versus inactive state is the switches in MRAS. When MRAS is active, GTP is bound and the switches allow MRAS to be bound with PP1C. When MRAS is inactive, GDP is bound and the switches do not allow MRAS to bind to PP1C. The switches determine whether MRAS can bind to SHOC2-PP1C. The switches have to go through a conformational change to allow binding of SHOC2-PP1C to MRAS. The conformational change is needed because without it SHOC2-PP1C could bind to MRAS when MRAS is still inactive. This process would cause the SHOC2-PP1C-MRAS pathway to constantly be running. The switches and GDP/GTP help regulate this process.
-This conformational change is caused by GTP replacing GDP. When GTP is bound, MRAS shifts and binds with the previously associated SHOC2-PP1C complex. When GDP is bound, <scene name='95/952705/Switch_i_and_ii_with_gdp/8'>switch II</scene> in MRAS is moved outward, which causes a steric clash with SHOC2 <scene name='95/952705/Gdp_with_mras_and_shoc2/2'>(SHOC2 with Closed Switches)</scene>. When GTP is bound, <scene name='95/952705/Switch_i_and_ii_with_gtp/5'>Switch II</scene> in MRAS can form various hydrogen bonding, pi stacking and hydrophobic interactions with SHOC2<Ref name='Bonsor'>Daniel A. Bonsor, Patrick Alexander, Kelly Snead, Nicole Hartig, Matthew Drew, Simon Messing, Lorenzo I. Finci, Dwight V. Nissley, Frank McCormick, Dominic Esposito, Pablo Rodrigiguez-Viciana, Andrew G. Stephen, Dhirendra K. Simanshu. Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome. bioRxiv. 2022.05.10.491335. doi: 10.1101/2022.05.10.491335. [https://doi.org/10.1101/2022.05.10.491335. DOI:10.1101/2022.05.10.491335]. </Ref>. When MRAS is bound to SHOC2-PP1C, switch I has an important role in making interactions with PP1C<scene name='95/952705/Switch_i_and_ii_with_gtp/7'>(SHOC2 with Open Switches)</scene>. Though it is minute there is a change of the positioning of switch II when GDP vs GTP is bound.
+This conformational change is caused by GTP replacing GDP. When GTP is bound, MRAS shifts and binds with the previously associated SHOC2-PP1C complex. When GDP is bound, <scene name='95/952705/Switch_i_and_ii_with_gdp/8'>switch II</scene> in MRAS is moved outward, which causes a steric clash with SHOC2 <scene name='95/952705/Gdp_with_mras_and_shoc2/2'>(SHOC2 with Closed Switches)</scene>. When GTP is bound, <scene name='95/952705/Switch_i_and_ii_with_gtp/5'>switch II</scene> in MRAS can form various hydrogen bonding, pi stacking and hydrophobic interactions with SHOC2<Ref name='Bonsor'>Daniel A. Bonsor, Patrick Alexander, Kelly Snead, Nicole Hartig, Matthew Drew, Simon Messing, Lorenzo I. Finci, Dwight V. Nissley, Frank McCormick, Dominic Esposito, Pablo Rodrigiguez-Viciana, Andrew G. Stephen, Dhirendra K. Simanshu. Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome. bioRxiv. 2022.05.10.491335. doi: 10.1101/2022.05.10.491335. [https://doi.org/10.1101/2022.05.10.491335. DOI:10.1101/2022.05.10.491335]. </Ref>. When MRAS is bound to SHOC2-PP1C, switch I has an important role in making interactions with PP1C<scene name='95/952705/Switch_i_and_ii_with_gtp/7'>(SHOC2 with Open Switches)</scene>. Though it is minute there is a change of the positioning of switch II when GDP vs GTP is bound.
 ==Stabilizing Interactions in Ternary Complex==