Sandbox Reserved 1777: Difference between revisions

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[[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 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 (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>.

==PP1C==

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=Implications=

Because of this complex's key role in the regulation of the MAPK-RAF pathway, minor changes can be ~~deleterious~~. Unregulated activation of the MAPK pathway is known to be one of the most common causes of human cancer. This is due to unchecked cell division and proliferation which are the common trademarks of cancer. Cancer is thought to be so prevalent from this pathway because ~~it stabilizes~~ the interactions of the SMP complex ~~members and~~ consequently enhances holophosphatase activity <Ref name="Jajian" />.

Because of this complex's key role in the regulation of the MAPK-RAF pathway, minor changes can be drastic. Unregulated activation of the MAPK pathway is known to be one of the most common causes of human cancer. This is due to unchecked cell division and proliferation which are the common trademarks of cancer. Cancer is thought to be so prevalent from this pathway because mutations that stabilize the interactions of the SMP complex consequently enhances holophosphatase activity <Ref name="Jajian" />, leading to accelerated cell division.

The unregulated MAPK pathway is also thought to be responsible for a multitude of developmental disorders commonly known as RASopathies <Ref name="Lavoie" />. One such RASopathy caused by the mutation of a RAF kinase is known as [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422 Noonan Syndrome] (NS), which enhances complex formation. NS is a genetic disorder that can prevent normal development in different parts of the body in a variety of ways. Though specifics are related to the gene carrying the mutation, it can be characterized as having unusual facial characteristics, short stature, a variety of heart defects and disease, and other physical problems and developmental delays.

</StructureSection>

== References ==

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@@ Line 9: / Line 9: @@
 [[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 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 (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>.
 ==PP1C==
@@ Line 42: / Line 42: @@
 =Implications=
-Because of this complex's key role in the regulation of the MAPK-RAF pathway, minor changes can be deleterious. Unregulated activation of the MAPK pathway is known to be one of the most common causes of human cancer. This is due to unchecked cell division and proliferation which are the common trademarks of cancer. Cancer is thought to be so prevalent from this pathway because it stabilizes the interactions of the SMP complex members and consequently enhances holophosphatase activity <Ref name="Jajian" />.
+Because of this complex's key role in the regulation of the MAPK-RAF pathway, minor changes can be drastic. Unregulated activation of the MAPK pathway is known to be one of the most common causes of human cancer. This is due to unchecked cell division and proliferation which are the common trademarks of cancer. Cancer is thought to be so prevalent from this pathway because mutations that stabilize the interactions of the SMP complex consequently enhances holophosphatase activity <Ref name="Jajian" />, leading to accelerated cell division.
 The unregulated MAPK pathway is also thought to be responsible for a multitude of developmental disorders commonly known as RASopathies <Ref name="Lavoie" />. One such RASopathy caused by the mutation of a RAF kinase is known as [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422 Noonan Syndrome] (NS), which enhances complex formation. NS is a genetic disorder that can prevent normal development in different parts of the body in a variety of ways. Though specifics are related to the gene carrying the mutation, it can be characterized as having unusual facial characteristics, short stature, a variety of heart defects and disease, and other physical problems and developmental delays.
 </StructureSection>
 == References ==
 <references/>