Sandbox Reserved 1767: Difference between revisions

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===Cancer and Rasopathies=== should we intersperse this?

Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</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. Mutations in PP1C can trigger increased active site activity, increasing the RAF proteins that are active and available to bind to RAS. Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to cancer and/or RASopathies.

Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the Q249K 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, released an additional 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 Q71R mutation locked in GTP-induced RAS conformational changes.<ref name="Hauseman">PMID:35830882</ref>

MRAS G23V (equivalent to the oncogenic G13V in RAS), like MRAS Q71L (Q61L in RAS), also shows increased interaction with other effectors such as BRAF, CRAF, and AF6 (Fig. 6C), consistent with activating mutations leading to GTP-loading of MRAS (13). '''(THIS WILL BE A GREEN LINK)'''

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 Noonan Syndrome, a disease in the rasopathy family, point mutations G23V and T68I in MRAS were identified, however, the outcome of these 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 cancer and/or RASopathies.

Sandbox Reserved 1767: Difference between revisions

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 ===Cancer and Rasopathies=== should we intersperse this?
-Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</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. Mutations in PP1C can trigger increased active site activity, increasing  the RAF proteins that are active and available to bind to RAS. Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to cancer and/or RASopathies.
+Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the Q249K 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, released an additional 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 Q71R mutation locked in GTP-induced RAS conformational changes.<ref name="Hauseman">PMID:35830882</ref>
+MRAS G23V (equivalent to the oncogenic G13V in RAS), like MRAS Q71L (Q61L in RAS), also shows increased interaction with other effectors such as BRAF, CRAF, and AF6 (Fig. 6C), consistent with activating mutations leading to GTP-loading of MRAS (13). '''(THIS WILL BE A GREEN LINK)'''
+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 Noonan Syndrome, a disease in the rasopathy family, point mutations G23V and T68I in MRAS were identified, however, the outcome of these 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 cancer and/or RASopathies.