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Introduction
Biological Introduction
SHOC2-PP1C-MRAS is a human enzyme that is involved in regulating cell proliferation and division[1]. 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[1] such as HRAS, NRAS, or KRAS. RAS-GTPases are a family of proteins that work by functioning as molecular switches[2]. This occurs from the protein alternating between binding GTP to be active and GDP to be inactive [1]. After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which activates RAF[2].
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 holoenzyme [3]. SHOC-2 is a scaffolding protein scaffolding protein 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[3], 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[3]. 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.
Sources
Liau [4]
Hauseman[3]
Kwon [5]
Lavoie [6]
Abstract LB029[7]
Bonsor[8]
Young(MRAS section) [9]
Kwon and Hahn (SHOC2 section) [10]
Relevance
Structural highlights
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- ↑ 1.0 1.1 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. DOI:10.1042/BST20211166.
- ↑ Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006 Jan;1(1):7-9. DOI:10.1016/S1556-0864(15)31506-9.
- ↑ 3.0 3.1 3.2 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. DOI:10.1038/s41586-022-05086-1.
- ↑ 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. DOI:10.1038/s41586-022-04838-3.
- ↑ 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. DOI:10.1038/s41586-022-04928-2.
- ↑ Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signalling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7.
- ↑ 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. DOI: 10.1158/1538-7445.AM2022-LB029.
- ↑ 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. DOI: 10.1038/s41594-022-00841-4.
- ↑ 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. DOI: 0.1101/cshperspect.a033621.
- ↑ 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. DOI: 10.1128/MCB.00627-20.
