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<StructureSection load='7pui' size='350' side='right' caption='SHOC2-PP1C-MRAS (PDB entry [[7pui]])' scene='95/952704/Smpcolored/1'>
<StructureSection load='7pui' size='350' side='right' caption='SHOC2-PP1C-MRAS (PDB entry [[7pui]])' scene='95/952704/Smpcolored/1'>
=Introduction=
=Introduction=
[[Image: Image 4-3-23 at 10.02 AM.jpeg|300px|right|thumb|<font size="3.5"><div style="text-align: center;">Schematic representation of SHOC2-PP1C-MRAS pathway after all domains are bound together. </div></font>]]
[[Image: Image 4-3-23 at 10.02 AM.jpeg|300px|right|thumb|<font size="3.5"><div style="text-align: center;">'''Figure 1'''. Schematic representation of SHOC2-PP1C-MRAS pathway after all domains are bound together. </div></font>]]


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 [https://www.mechanobio.info/what-is-mechanosignaling/what-are-small-gtpases/what-are-ras-gtpases/. GTPase] such as HRAS, NRAS, or KRAS. [https://www.frontiersin.org/articles/10.3389/fonc.2019.01088/full#:~:text=In%20human%20cells%2C%20three%20closely,proliferation%20and%20survival%20among%20others. 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311149/#:~:text=Full%20activation%20of%20Raf%20requires,plasma%20membrane%20(Roy%20et%20al 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> by phosphorylating the serine 259 residue. RAF triggers a series of downstream signaling pathways including MEK and ERK. The Ras/Raf/MEK/ERK pathway is a critical signaling cascade for activating transcription factors and regulating gene expression<Ref name='Li'>Li, L., Zhao, G. D., Shi, Z. et. al.The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncology letters, 12(5), 3045–3050. [https://doi.org/10.3892/ol.2016.5110. DOI:10.3892/ol.2016.5110]. </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 [https://www.mechanobio.info/what-is-mechanosignaling/what-are-small-gtpases/what-are-ras-gtpases/. GTPase] such as HRAS, NRAS, or KRAS. [https://www.frontiersin.org/articles/10.3389/fonc.2019.01088/full#:~:text=In%20human%20cells%2C%20three%20closely,proliferation%20and%20survival%20among%20others. 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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311149/#:~:text=Full%20activation%20of%20Raf%20requires,plasma%20membrane%20(Roy%20et%20al 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> by phosphorylating the serine 259 residue. RAF triggers a series of downstream signaling pathways including MEK and ERK. The Ras/Raf/MEK/ERK pathway is a critical signaling cascade for activating transcription factors and regulating gene expression<Ref name='Li'>Li, L., Zhao, G. D., Shi, Z. et. al.The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncology letters, 12(5), 3045–3050. [https://doi.org/10.3892/ol.2016.5110. DOI:10.3892/ol.2016.5110]. </Ref>.  
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=Structure=
=Structure=
==Overview==
==Overview==
[[Image:SHOC2-PP1C-MRAS Surface.JPG|300px|right|thumb|<font size="3.5"><div style="text-align: center;">'''Figure 1'''. Surface representation of SHOC2-PP1C-MRAS from PDB 7pui. Blue is SHOC2, orange is PP1C and green is MRAS.  </div></font>]]


The enzyme requires 3 domains, SHOC2(blue), PP1C(orange), and MRAS(green), to form the active enzyme (SMP complex), also known as a holoenzyme (Figure 1)<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>. 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 enzyme requires 3 domains, SHOC2(blue), PP1C(orange), and MRAS(green), to form the active enzyme (SMP complex), also known as a holoenzyme (Figure 1)<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>. 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.


==SHOC2==
==SHOC2==
[[Image:SHOC2-PP1C-MRAS Surface.JPG|300px|right|thumb|<font size="3.5"><div style="text-align: center;">'''Figure 2'''. Surface representation of SHOC2-PP1C-MRAS from PDB 7pui. Blue is SHOC2, orange is PP1C and green is MRAS.  </div></font>]]
SHOC2 is a scaffolding protein which acts as a cradle to bind PP1C and MRAS, allowing for the holoenzyme to be functional. The <scene name='95/952705/Shoc2_structure/1'>structure of SHOC2</scene> is a leucine rich repeat ([https://en.wikipedia.org/wiki/Leucine-rich_repeat LRR]) protein that consists of 20 consecutive <scene name='95/952706/Shoc2_structure/6'>LRR regions</scene>. This motif results in an extended beta sheet on the inner concavity of the protein surface with alpha helices facing outward. This results in a largely hydrophobic core<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>.
SHOC2 is a scaffolding protein which acts as a cradle to bind PP1C and MRAS, allowing for the holoenzyme to be functional. The <scene name='95/952705/Shoc2_structure/1'>structure of SHOC2</scene> is a leucine rich repeat ([https://en.wikipedia.org/wiki/Leucine-rich_repeat LRR]) protein that consists of 20 consecutive <scene name='95/952706/Shoc2_structure/6'>LRR regions</scene>. This motif results in an extended beta sheet on the inner concavity of the protein surface with alpha helices facing outward. This results in a largely hydrophobic core<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>.


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