Sandbox Reserved 1767: Difference between revisions

(5 intermediate revisions by the same user not shown)

Line 33:

==RAS==

RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. intracellular switches] that are anchored to the plasma membrane. <ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane ~~allowing~~ only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <ref name="Hauseman">PMID:35830882</ref>.

RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. intracellular switches] that are anchored to the plasma membrane. <ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane. This allows only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <ref name="Hauseman">PMID:35830882</ref>.

A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''', {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2 binding site}} colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|RAF binding site}} shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway <ref name="Lavoie">PMID: 35970881</ref>. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</scene> is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane.

MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS can lead to consistent GTP-loading, causing an increase in the formation of the SMP complex ~~and there is~~ consistent activation of the cell-proliferation pathway in the absence of external growth factors.

MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS can lead to consistent GTP-loading, causing an increase in the formation of the SMP complex as well as consistent activation of the cell-proliferation pathway in the absence of external growth factors.

Line 48:

=== Cancer and Rasopathies ===

Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, ~~that~~ can ~~lead to~~ [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692211/. higher binding affinity].<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the <scene name='95/952695/Q249k_mutation/1'>Q249K</scene> mutation because this creates a salt bridge with E116 of PP1C. This enhances the binding energy by -22.7 kcal/mol. ~~The G63R mutation on SHOC2 creates two additional hydrogen bonds with D242 on PP1C, releasing another 18.88kcal/mol of interaction energy.<ref name="Kwon">PMID: 35831509</ref>~~ Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. The majority of wild type MRAS in cells ~~were in the~~ GDP ~~state~~, whereas the MRAS with the Q71L mutation locked in GTP~~-induced RAS conformational changes~~.<ref name="Hauseman">PMID:35830882</ref> In MRAS, <scene name='95/952695/Q249k_mutation/2'>Q71L and G23V</scene> both show increased interaction with other effectors such as BRAF, CRAF, and AF6, consistent with gain-of-function mutations that activate MRAS, leading to GTP-loading.

Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, which can result in [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692211/. higher binding affinity].<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the <scene name='95/952695/Q249k_mutation/1'>Q249K</scene> mutation because this creates a salt bridge with E116 of PP1C. This enhances the binding energy by -22.7 kcal/mol. Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. The majority of wild type MRAS in cells are bound to GDP, whereas the MRAS with the Q71L mutation locked MRAS in the GTP bound state.<ref name="Hauseman">PMID:35830882</ref> In MRAS, <scene name='95/952695/Q249k_mutation/2'>Q71L and G23V</scene> both show increased interaction with other effectors such as BRAF, CRAF, and AF6, consistent with gain-of-function mutations that activate MRAS, leading to GTP-loading.

Mutations in PP1C can trigger increased active site activity, increasing the RAF proteins that are active and available to bind to RAS. In patients with [https://medlineplus.gov/genetics/condition/noonan-syndrome/#:~:text=Noonan%20syndrome%20is%20a%20condition,many%20other%20signs%20and%20symptoms. Noonan Syndrome], a disease in the RASopathy family, a point mutation of <scene name='95/952695/Q249k_mutation/2'>T68I</scene> MRAS was identified, however, the ~~outcome is~~ unknown.<ref name="Young">PMID: 30348783</ref> Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to [https://www.ncbi.nlm.nih.gov/books/NBK20362/. cancer] and/or RASopathies.

Mutations in PP1C can trigger increased active site activity, increasing the RAF proteins that are active and available to bind to RAS. In patients with [https://medlineplus.gov/genetics/condition/noonan-syndrome/#:~:text=Noonan%20syndrome%20is%20a%20condition,many%20other%20signs%20and%20symptoms. Noonan Syndrome], a disease in the RASopathy family, a point mutation of <scene name='95/952695/Q249k_mutation/2'>T68I</scene> MRAS was identified, however the effects this has are unknown.<ref name="Young">PMID: 30348783</ref> Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to [https://www.ncbi.nlm.nih.gov/books/NBK20362/. cancer] and/or RASopathies.

Sandbox Reserved 1767: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 33: / Line 33: @@
 ==RAS==
-RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. intracellular switches] that are anchored to the plasma membrane. <ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane allowing only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <ref name="Hauseman">PMID:35830882</ref>.
+RAS proteins are GTP-dependent [https://pubmed.ncbi.nlm.nih.gov/14604583/. intracellular switches] that are anchored to the plasma membrane. <ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004624/. dissociation constant] <ref name="Liau">PMID: 35768504</ref>. There are no known membrane interacting regions on SHOC2 and PP1C, meaning the [https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/03%3A_Biological_Macromolecules/3.05%3A_Lipid_Molecules_-_Phospholipids#:~:text=The%20fatty%20acid%20chains%20are,the%20intracellular%20and%20extracellular%20fluid. hydrophobic fatty acid tail] on MRAS is responsible for recruiting the complex to the cell membrane. This allows only for 2D movement and increasing local concentrations of the players needed in this signaling pathway <ref name="Hauseman">PMID:35830882</ref>.
 A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and RAF <ref name="Liau">PMID: 35768504</ref>. In '''Figure 3''',  {{Font color|lime|MRAS}} is shown in green, with the {{Font color|cyan|SHOC2 binding site}} colored cyan, the {{Font color|violet|PP1C binding site}} colored violet, and the {{Font color|red|RAF binding site}} shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway <ref name="Lavoie">PMID: 35970881</ref>. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF <ref name="Lavoie">PMID: 35970881</ref>. The ability of MRAS-GTP to cluster at the cell membrane is a crucial capability for this protein complex. The presence of this <scene name='95/952695/413cellmemprotrusion/4'>palmitoylated tail</scene> is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane.
-MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS can lead to consistent GTP-loading, causing an increase in the formation of the SMP complex and there is consistent activation of the cell-proliferation pathway in the absence of external growth factors.
+MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS can lead to consistent GTP-loading, causing an increase in the formation of the SMP complex as well as consistent activation of the cell-proliferation pathway in the absence of external growth factors.
@@ Line 48: / Line 48: @@
 === Cancer and Rasopathies ===
-Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692211/. higher binding affinity].<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the <scene name='95/952695/Q249k_mutation/1'>Q249K</scene> mutation because this creates a salt bridge with E116 of PP1C. This enhances the binding energy by -22.7 kcal/mol. The G63R mutation on SHOC2 creates two additional hydrogen bonds with D242 on PP1C, releasing another 18.88kcal/mol of interaction energy.<ref name="Kwon">PMID: 35831509</ref> Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. The majority of wild type MRAS in cells were in the GDP state, whereas the MRAS with the Q71L mutation locked in GTP-induced RAS conformational changes.<ref name="Hauseman">PMID:35830882</ref> In MRAS, <scene name='95/952695/Q249k_mutation/2'>Q71L and G23V</scene> both show increased interaction with other effectors such as BRAF, CRAF, and AF6, consistent with gain-of-function mutations that activate MRAS, leading to GTP-loading.
+Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, which can result in [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692211/. higher binding affinity].<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the <scene name='95/952695/Q249k_mutation/1'>Q249K</scene> mutation because this creates a salt bridge with E116 of PP1C. This enhances the binding energy by -22.7 kcal/mol. Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. The majority of wild type MRAS in cells are bound to GDP, whereas the MRAS with the Q71L mutation locked MRAS in the GTP bound state.<ref name="Hauseman">PMID:35830882</ref> In MRAS, <scene name='95/952695/Q249k_mutation/2'>Q71L and G23V</scene> both show increased interaction with other effectors such as BRAF, CRAF, and AF6, consistent with gain-of-function mutations that activate MRAS, leading to GTP-loading.
-Mutations in PP1C can trigger increased active site activity, increasing  the RAF proteins that are active and available to bind to RAS. In patients with [https://medlineplus.gov/genetics/condition/noonan-syndrome/#:~:text=Noonan%20syndrome%20is%20a%20condition,many%20other%20signs%20and%20symptoms. Noonan Syndrome], a disease in the RASopathy family, a point mutation of <scene name='95/952695/Q249k_mutation/2'>T68I</scene> MRAS was identified, however, the outcome is unknown.<ref name="Young">PMID: 30348783</ref> Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to [https://www.ncbi.nlm.nih.gov/books/NBK20362/. cancer] and/or RASopathies.
+Mutations in PP1C can trigger increased active site activity, increasing  the RAF proteins that are active and available to bind to RAS. In patients with [https://medlineplus.gov/genetics/condition/noonan-syndrome/#:~:text=Noonan%20syndrome%20is%20a%20condition,many%20other%20signs%20and%20symptoms. Noonan Syndrome], a disease in the RASopathy family, a point mutation of <scene name='95/952695/Q249k_mutation/2'>T68I</scene> MRAS was identified, however the effects this has are unknown.<ref name="Young">PMID: 30348783</ref> Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to [https://www.ncbi.nlm.nih.gov/books/NBK20362/. cancer] and/or RASopathies.