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=== Biological Introduction ===
=== Biological Introduction ===
SHOC2-PP1C-MRAS is a human enzyme that is involved in regulating cell proliferation and division<ref name=”Astrain”>PMID:35356965</ref>. The enzyme is involved in the vast RAS-MAPK pathway, which is initially activated by an extracellular growth factor binding to a membrane bound RAS GTPase[https://www.mechanobio.info/what-is-mechanosignaling/what-are-small-gtpases/what-are-ras-gtpases/] such as HRAS, NRAS, or KRAS. RAS-GTPases are a family of proteins that work by functioning as molecular switches. This occurs from the protein alternating between binding GTP to be active and GDP to be inactive <ref name="Astrain" />. After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which activates RAF<ref>DOI:10.1016/S1556-0864(15)31506-9</ref>.
SHOC2-PP1C-MRAS is a human enzyme that is involved in regulating cell proliferation and division<Ref name='Astrain'>Bernal Astrain G, Nikolova M, Smith MJ. Functional diversity in the RAS subfamily of small GTPases. Biochem Soc Trans. 2022 Apr 29;50(2):921-933. doi: 10.1042/BST20211166. [https://doi.org/10.1042/BST20211166. DOI:10.1042/BST20211166]. </Ref>. The enzyme is involved in the vast RAS-MAPK pathway, which is initially activated by an extracellular growth factor binding to a membrane bound RAS GTPase[https://www.mechanobio.info/what-is-mechanosignaling/what-are-small-gtpases/what-are-ras-gtpases/] such as HRAS, NRAS, or KRAS. RAS-GTPases are a family of proteins that work by functioning as molecular switches[https://www.frontiersin.org/articles/10.3389/fonc.2019.01088/full#:~:text=In%20human%20cells%2C%20three%20closely,proliferation%20and%20survival%20among%20others]. This occurs from the protein alternating between binding GTP to be active and GDP to be inactive <ref name="Astrain" />. After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which activates RAF<Ref name='Molina'>Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006 Jan;1(1):7-9. [https://doi.org/10.1016/S1556-0864(15)31506-9. DOI:10.1016/S1556-0864(15)31506-9]. </Ref>.


=== Structural Introduction ===
=== Structural Introduction ===
The enzyme requires 3 domains (SHOC-2(blue), PP1C(coral), and MRAS (green)) to form the active enzyme (SMP Complex), also known as a <scene name='95/952704/Smpcolored/1'>holoenzyme </scene> <Ref name='Hauseman'>Hauseman, Z.J., Fodor, M., Dhembi, A. et al. Structure of the MRAS–SHOC2–PP1C phosphatase complex. Nature 609, 416–423 (2022). doi: 10.1038/s41586-022-05086-1. [https://doi.org/10.1038/s41586-022-05086-1. DOI:10.1038/s41586-022-05086-1]. </Ref>. SHOC-2 is a scaffolding protein <scene name='95/952704/Shoc2_cradle/1'>scaffolding protein</scene> that holds the other subunits in the correct orientation, allowing for the holoenzyme to be functional. PP1C is a catalytic domain of a phosphatase enzyme PP1[https://proteopedia.org/wiki/index.php/Protein_phosphatase], which cleaves ____. MRAS is a GTPase protein and is located near (typically just below) the cell membrane. When MRAS binds GTP, it becomes active and triggers the assembly of the active holoenzyme<ref name="Hauseman" />. The SMP complex was determined via cryo-electron microscopy as well as x-ray diffraction. These studies found that PP1C and MRAS occupy the concave surface of SHOC2, leaving the catalytic site of PP1C and the substrate binding cleft in MRAS exposed.


The active holoenzyme contains 3 domains. The SHOC-2(blue), PP1C(coral), and MRAS (green) domains form the complete <scene name='95/952704/Smpcolored/1'>SMP complex. </scene>
== Sources ==
Liau <Ref name='Liau'>Liau, N.P.D., Johnson, M.C., Izadi, S. et al. Structural basis for SHOC2 modulation of RAS signalling. Nature 609, 400–407 (2022).doi: 10.1038/s41586-022-04838-3. [https://doi.org/10.1038/s41586-022-04838-3. DOI:10.1038/s41586-022-04838-3]. </Ref>


SHOC-2 is a scaffolding protein <scene name='95/952704/Shoc2_cradle/1'>scaffolding protein</scene> that holds the other subunits in the correct orientation, allowing for the holoenzyme to be functional.  
Hauseman<ref name="Hauseman" />
 
Kwon <Ref name='Kwon'>Kwon, J.J., Hajian, B., Bian, Y. et al. Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex. Nature 609, 408–415 (2022).doi: 10.1038/s41586-022-04928-2. [https://doi.org/10.1038/s41586-022-04928-2. DOI:10.1038/s41586-022-04928-2]. </Ref>
 
Lavoie <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signalling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>
 
Abstract LB029<Ref name= 'Jajian'>Kwon, J., Jajian, B., Bian, Y. et al. Comprehensive structure-function evaluation of the SHOC2 holophosphatase reveals disease mechanisms and therapeutic opportunities. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022. [https://aacrjournals.org/cancerres/article/82/12_Supplement/LB029/699443. DOI: 10.1158/1538-7445.AM2022-LB029]. </Ref>
 
Bonsor<Ref name= 'Bonsor'>Bonsor, D., Alexander, P., Snead, K. et al. Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome.  Nat Struct Mol Biol 29, 966–977 (2022). doi:10.1038/s41594-022-00841-4. [https://doi.org/10.1038/s41594-022-00841-4. DOI: 10.1038/s41594-022-00841-4]. </Ref>
 
Young(MRAS section) <Ref name= 'Young'>Young, L., Rodriguez-Viciana, P. MRAS: A Close but Understudied Member of the RAS Family. Cold Spring Harbor Perspectives in Medicine (2018). doi: 10.1101/cshperspect.a033621. [https://perspectivesinmedicine.cshlp.org/content/8/12/a033621.full.pdf+html. DOI: 0.1101/cshperspect.a033621]. </Ref>
 
Kwon and Hahn (SHOC2 section) <Ref name= 'Hahn'> Kwon, J. J., & Hahn, W. C. A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective. Molecular and cellular biology, 41(4), e00627-20 (2021). doi:10.1128/MCB.00627-20. [http://doi.org/10.1128/MCB.00627-20. DOI: 10.1128/MCB.00627-20]. </Ref>
 
PP1C section [https://www.ncbi.nlm.nih.gov/gene/5499 external link]
 
blue link LRR [https://en.wikipedia.org/wiki/Leucine-rich_repeat LRR]
 
Arkun (for ERK signaling) <Ref name= 'Arkun'> Arkun, Y., & Yasemi, M. Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations. PloS one, 13(4), e0195513. doi: 10.1371/journal.pone.0195513 [https://doi.org/10.1371/journal.pone.0195513. DOI: 10.1371/journal.pone.0195513]. </Ref>
 
For last sentence in implications van der Burgt <Ref name= 'van der Burgt'> van der Burgt, I. Noonan syndrome. Orphanet J Rare Dis 2, 4 (2007). doi: 10.1186/1750-1172-2-4 [https://doi.org/10.1186/1750-1172-2-4. DOI: 10.1186/1750-1172-2-4]. </Ref>
 
PP1C REF: <Ref name= 'Aggen'> Aggen, J., Nairn, A., Chamberlin, R. Regulation of protein phosphatase-1. Chemistry & Biology 2000, 7:R13–R23. [https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(00)00069-7.pdf]. </Ref>.


== Biological Function ==


== Relevance ==
== Relevance ==
test reference<Ref name='Molina'>Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006 Jan;1(1):7-9. [https://doi.org/10.1016/S1556-0864(15)31506-9. DOI:10.1016/S1556-0864(15)31506-9]. </Ref>
 
== Structural highlights ==
== Structural highlights ==


This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.


</StructureSection>
</StructureSection>
== References ==
== References ==
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