Sandbox Reserved 1777: Difference between revisions
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=Structure= | =Structure= | ||
==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 7up1. Blue is SHOC2, orange is PP1C and green is MRAS. </div></font>]] | [[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 7up1. Blue is SHOC2, orange is PP1C and green is MRAS. </div></font>]] | ||
The enzyme requires 3 domains, SHOC-2(blue), PP1C(coral), 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, SHOC-2(blue), PP1C(coral), 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== | ||
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/ | 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. | ||
==PP1C== | ==PP1C== | ||
<scene name='95/ | <scene name='95/952705/Pp1c_structure/1'>PP1C</scene> is a catalytic domain of a phosphatase enzyme [https://proteopedia.org/wiki/index.php/Protein_phosphatase. PP1], which cleaves a phosphate. This subunit is a serine/threonine phosphatase known to be involved in a variety of cellular signalling pathways that control cell growth, division, and metabolism (again cite, see texts). | ||
==MRAS== | ==MRAS== | ||
<scene name='95/952705/Mras_structure/ | <scene name='95/952705/Mras_structure/4'>MRAS</scene> 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" />. MRAS is a close relative of the RAS protein and therefore shares most of it's regulatory and effector interactions (CITE, see text from emily lol). A unique function of MRAS is it's ability to form a complex with SHOC2 and PP1, allowing it to have phosphatase activity. | ||
===Switch I and II=== | ===Switch I and II=== | ||
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==Special Interactions== | ==Special Interactions== | ||
MRAS binds to SHOC2 exclusively through this concave region <Ref name='Kwan'>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>, primarily by the descending loop and strands of each LRR domains 2-10. This reaction is stabilized through <scene name='95/952705/ | MRAS binds to SHOC2 exclusively through this concave region <Ref name='Kwan'>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>, primarily by the descending loop and strands of each LRR domains 2-10. This reaction is stabilized through <scene name='95/952705/Shoc2_mras_interaction/2'>hydrogen bonding</scene> between residues of each subunit. <scene name='95/952705/Shoc2_pp1c_interaction/1'>PP1C binds</scene> with the ascending loops of the SHOC2 LRR regions, and is further engaged through the N-terminal region containing the <scene name='95/952705/Shoc2_rvxf/3'>PVxF motif</scene> <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>. The initial forming of the complex begins with SHOC2:PP1C engagement, then is completed and stabilized by the GTP-loaded MRAS binding <Ref name="Jajian" />. Once associated with SHOC2, <scene name='95/952705/Mras_pp1c_interaction/2'>MRAS binds to PP1C</scene> and guides the holoenzyme complex to the cell membrane to begin signaling<ref name="Kwan" />. | ||
=Mechanism= | =Mechanism= | ||
