Sandbox Reserved 1789: Difference between revisions
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<scene name='95/952717/Shoc2/1'>SHOC2</scene> is a scaffold protein composed of 20 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901792/. leucine-rich repeat (LRR)] domains that form a solenoid structure <ref name="Hauseman"/>. The leucine rich region forms a concave hydrophobic core which is necessary for binding with PP1C and MRAS. SHOC2 is the crucial mediator for SHOC2-PP1C-MRAS complex formation <ref name="Hauseman"/>. The leucine rich domain is very important in creating selectivity for the PP1C protein, as that protein is used for so many other complex pathways <ref name="Hauseman"/>. The LRR domains are stabilized by an N-terminal flanking 𝝰-helix and a C-terminal helix-turn-helix <ref name="Kwon">PMID:35831509</ref>. Alongside the conserved leucine residues in the LRR domain, there is a group of conserved asparagine residues that creates a stabilizing [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184636/. “asparagine ladder”] that is necessary for the LRR fold, giving the SHOC2 its concave structure <ref name="Kwon" />. | <scene name='95/952717/Shoc2/1'>SHOC2</scene> is a scaffold protein composed of 20 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901792/. leucine-rich repeat (LRR)] domains that form a solenoid structure <ref name="Hauseman"/>. The leucine rich region forms a concave hydrophobic core which is necessary for binding with PP1C and MRAS. SHOC2 is the crucial mediator for SHOC2-PP1C-MRAS complex formation <ref name="Hauseman"/>. The leucine rich domain is very important in creating selectivity for the PP1C protein, as that protein is used for so many other complex pathways <ref name="Hauseman"/>. The LRR domains are stabilized by an N-terminal flanking 𝝰-helix and a C-terminal helix-turn-helix <ref name="Kwon">PMID:35831509</ref>. Alongside the conserved leucine residues in the LRR domain, there is a group of conserved asparagine residues that creates a stabilizing [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184636/. “asparagine ladder”] that is necessary for the LRR fold, giving the SHOC2 its concave structure <ref name="Kwon" />. | ||
SHOC2 is also capable of causing various forms of | SHOC2 is also capable of causing various forms of cancers and rasopathies. A common one is caused by a mutation known as p.S2G <ref name="Rauen">Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-69. [http://dx.doi.org/10.1146/annurev-genom-091212-153523 doi: 10.1146/annurev-genom-091212-153523.]</ref>. This mutation causes the formation of an additional 14-carbon saturated fatty acid chain on the N-terminal glycine of SHOC2 <ref name="Rauen" />. This causes SHOC2 to become attached to the cell membrane, resulting in a prolonged dephosphorylation of RAF by PP1C <ref name="Rauen" />. With this abnormality, there is overexpression of the MAPK pathway and increased cell proliferation genes <ref name="Rauen" />. This can cause the formation of various tumors in the body. Other mutations of the SMP ternary structure as a whole can also lead to the development of Noonan syndrome <ref name="Hauseman"/>. | ||
=== PP1C === | === PP1C === | ||
<scene name='95/952717/Pp1c/2'>PP1C</scene> is a phosphatase. After forming a ternary complex, the hydrophobic active site on PP1C interacts with Raf and dephosphorylate Ser 259. PP1C's active site is adjacent to a hydrophobic binding pocket that binds to the C-terminal phosphoserine, located on the N-terminus of RAF, the target for dephosphorylation. PP1C can act as a phosphatase in the absence of SHOC2 but PP1C lacks intrinsic substrate selectively. The SMP complex formation endows PP1C with specificity for RAF <ref name="Hauseman" />. | <scene name='95/952717/Pp1c/2'>PP1C</scene> is a phosphatase. After forming a ternary complex, the hydrophobic active site on PP1C interacts with Raf and dephosphorylate Ser 259. PP1C's active site is adjacent to a hydrophobic binding pocket that binds to the C-terminal phosphoserine, located on the N-terminus of RAF, the target for dephosphorylation. PP1C can act as a phosphatase in the absence of SHOC2 but PP1C lacks intrinsic substrate selectively. The SMP complex formation endows PP1C with specificity for RAF <ref name="Hauseman" />. | ||
The mechanism that PP1C uses to catalyze the dephosphorylation is mainly through donating a hydrogen atom to a phosphate group on the C-terminal of a | The mechanism that PP1C uses to catalyze the dephosphorylation is mainly through donating a hydrogen atom to a phosphate group on the C-terminal of a phosphoserine on Raf <ref name="Kubicek"/>. This makes the phosphate group a good leaving group and it breaks off <ref name="Kubicek"/>. This catalysis is done by the serine-threonine alpha catalytic site on PP1C <ref name="Kubicek"/>. In this catalytic site, there are two Manganese ions and one calcium ion <ref name="Kubicek"/>. These metal ions are necessary in stablizing this catalytic site and there are a lot of polar negative residues in this region <ref name="Kubicek"/>. | ||
The catalytic site is also capable of causing various rasopathies if there is a mutation present <ref name="Rauen" />. Typically the mutation is centered around the catalytic site not being able to attach to the dephosphorylation site on Ras <ref name="Rauen" />. This causes an underproduction of cell proliferation pathways and leads to Rasopathies. RASopathy is a broad term used to describe developmental syndromes that stem from germline mutations of proteins along the RAS/MAPK pathway. These mutations can be either gain or loss of function. Rasopathies can also lead to cancer <ref name="Rauen" />. The mutation in PP1C can result in damages in growth and development in multiple areas of the body .<ref name="Rauen" /> | |||