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This page, as it appeared on March 17, 2023, was featured in this article in the journal Biochemistry and Molecular Biology Education.

SHOC2-PP1C-MRAS

1 Introduction
2 Overall Structure
3 Signaling Pathway
4 Disease Relevance
- 4.1 Cancer
- 4.2 RASopathies
5 Future Studies
6 3D structures of lysophosphatidic acid receptor
7 References
8 Student Contributors

Introduction

SHOC2-PP1C-MRAS is a ternary complex formed by the individual proteins: SHOC2, PP1C, and MRAS. Formation of this complex begins with a signal binding to a receptor tyrosine kinase receptor(RTK). This causes membrane bound MRAS to exchange GDP for GTP. From here the complex comes together and is able to dephosphorylate the RAF complex leading to further downstream signaling effects.

Overall Structure

SHOC2

PP1C

MRAS

is a membrane bound structure that aids the complex in localizing near other structures such as the RAS-RAF-MAPK complex in order to initiate downstream signaling. In its inactive state, MRAS is bound to GDP. When signaled by growth factors, the GDP is exchanged for GTP. The now undergoes a conformational change of the switch I and switch II regions. This conformational change activates the protein allowing it to bind more easily with the SHOC2-PP1C complex. In comparison to other RAS proteins, MRAS has a greater affinity for the SHOC2-PP1C complex.

Key Ligand Interactions

SHOC2 and PP1C

PP1C binds to SHOC2 on its leucine rich region(LRR). Specifically, on two broad surfaces between LRR2 and LRR5 and between LRR7 and LRR11. Five main hydrogen bonds are made: E56-R182, E167-R203, E54-K180, R187-H178, R188-E155. The binding regions can also be shown as acidic and basic patches on and . The corresponding patches interact to form a .

SHOC2 and MRAS

MRAS is initially bound to GDP causing it to be in its inactive state. This form cannot bind to the SHOC2-PP1C complex due to steric clashing. Once GDP is exchanged for GTP to activate the protein, conformational changed occur withing the switch I and switch II regions to allow MRAS to interact with SHOC2. These interactions include hydrogen bonds of and pi stacking. The primary hydrogen bonds are R288-Q71 and R177-E47. Pi staking occurs at R104-R83.

PP1C and MRAS

The interactions between PP1C and MRAS are mediated by four main hydrogen bonds: R188-D48, M190-Q35, D197-H53, Q198-K36. It is unclear whether PP1C must bind to SHOC2 before MRAS binds or if PP1C and MRAS can bind to SHOC2 at the same time.

Signaling Pathway

Figure 1:Signaling cascade is shown with SHOC2 in pink, PP1C in blue, and MRAs in white.

Figure 2:PP1C dephosphorylates RAF protein at serine 259

Disease Relevance

Cancer

RASopathies

Future Studies

3D structures of lysophosphatidic acid receptor

4z34, 4z35, 4z36 - hLPA1 + antagonist - human
2lq4 – hLPA1 second extracellular loop – NMR
4p0c – hLPA2/NHERF2
5xsz – LPA6A (mutant) – zebra fish

References

^[1]. ^[2]. ^[3]. ^[4]. ^[5].

↑ Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Molle S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA. Structure of the MRAS-SHOC2-PP1C phosphatase complex. Nature. 2022 Jul 13. pii: 10.1038/s41586-022-05086-1. doi:, 10.1038/s41586-022-05086-1. PMID:35830882 doi:http://dx.doi.org/10.1038/s41586-022-05086-1
↑ Kubicek M, Pacher M, Abraham D, Podar K, Eulitz M, Baccarini M. Dephosphorylation of Ser-259 regulates Raf-1 membrane association. J Biol Chem. 2002 Mar 8;277(10):7913-9. PMID:11756411 doi:10.1074/jbc.M108733200
↑ Kwon JJ, Hajian B, Bian Y, Young LC, Amor AJ, Fuller JR, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Barsotti AM, Stamford AW, Perry CK, Burgin A, McCormick F, Lemke CT, Hahn WC, Aguirre AJ. Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature. 2022 Jul 13. pii: 10.1038/s41586-022-04928-2. doi:, 10.1038/s41586-022-04928-2. PMID:35831509 doi:http://dx.doi.org/10.1038/s41586-022-04928-2
↑ Lavoie H, Therrien M. Structural keys unlock RAS-MAPK cellular signalling pathway. Nature. 2022 Sep;609(7926):248-249. PMID:35970881 doi:10.1038/d41586-022-02189-7
↑ Liau NPD, Johnson MC, Izadi S, Gerosa L, Hammel M, Bruning JM, Wendorff TJ, Phung W, Hymowitz SG, Sudhamsu J. Structural basis for SHOC2 modulation of RAS signalling. Nature. 2022 Jun 29. pii: 10.1038/s41586-022-04838-3. doi:, 10.1038/s41586-022-04838-3. PMID:35768504 doi:http://dx.doi.org/10.1038/s41586-022-04838-3

Student Contributors

Madeline Gilbert Inaya Patel Rushda Hussein

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@@ Line 29: / Line 29: @@
 === SHOC2 and PP1C ===
+<scene name='95/952717/Shoc2_and_pp1c/1'>Shoc2-PP1C</scene>
+<scene name='95/952717/Shoc2_and_pp1c/2'>SHOC2-PP1C Binding Pocket</scene>
 PP1C binds to SHOC2 on its leucine rich region(LRR). Specifically, on two broad surfaces between LRR2 and LRR5 and between LRR7 and LRR11. Five main hydrogen bonds are made: E56-R182, E167-R203, E54-K180, R187-H178, R188-E155. The binding regions can also be shown as acidic and basic patches on <scene name='95/952718/Acid_base_pp1c/1'>PP1C</scene> and <scene name='95/952718/Acid_base_shoc2/1'>SHOC2</scene>. The corresponding patches interact to form a <scene name='95/952718/Acid_base_shoc2pp1c/1'>binary complex</scene>.
 === SHOC2 and MRAS ===
 MRAS is initially bound to GDP causing it to be in its inactive state. This form cannot bind to the SHOC2-PP1C complex due to steric clashing. Once GDP is exchanged for GTP to activate the protein, conformational changed occur withing the switch I and switch II regions to allow MRAS to interact with SHOC2. These interactions include hydrogen bonds of and pi stacking. The primary hydrogen bonds are R288-Q71 and R177-E47. Pi staking occurs at R104-R83.