Sandbox Reserved 1767: Difference between revisions

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.

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.  

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.