Sandbox Reserved 1777: Difference between revisions
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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 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='95/952706/Shoc2_structure/7'>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== | ||
Protein phosphatase 1 catalytic subunit is a catalytic domain of a phosphatase enzyme [https://proteopedia.org/wiki/index.php/Protein_phosphatase. PP1], which cleaves a phosphate. <scene name='95/952706/Pp1c_structure/3'>PP1C</scene> is a highly characterized serine/ threonine phosphatase. PP1C 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/1'>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== | ||
binds to SHOC2 exclusively through this concaved 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_structure/3'>hydrogen bonding</scene>. PP1C <scene name='95/952706/Shoc2_pp1c_interaction/2'>associates</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/1'>RVxF</scene> motif <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 MRAS has associated with SHOC2, it <scene name='95/952705/Mras_pp1c_interaction/1'>binds</scene> to PP1C and guides the holoenzyme complex to the cell membrane to begin signaling<ref name="Kwan" />. | |||
=Mechanism= | =Mechanism= | ||
