Sandbox Reserved 1789

Introduction

(SMP) is a ternary holophosphotase complex formed by the individual proteins: SHOC2, PP1C, and MRAS. The SMP complex is involved in signaling the initiation of MAPK pathways, which is responsible for cellular growth and development, cell proliferation, and apoptosis ^[1]. Formation of this complex begins with an extracellular signal binding to a membrane embedded receptor tyrosine kinase receptor(RTK) ^[1]. This causes membrane-bound MRAS to exchange GDP for GTP. Initiating the SMP complex formation at the plasma membrane consists of the SHOC2 and PP1C binding first. When the MRAS exchanges GDP to GTP, it then assembles with the combined SHOC2 and PP1C. Based on MRAS targeting, PP1C catalyzes the dephosphorylation of the N-terminal phosphoserine (NTpS) on the RAF complex leading to the amplification of MAPK signaling ^[1]. In a normal cell, this would regulate cell proliferation but dysfunction in the ternary complex has shown signs to lead to tumor formation due to unregulated cell growth ^[1].

Figure 1: Mechanism for Shoc2-MRAS-PP1C

Figure 2: PP1C phosphorylates Serine 259.

Overall Structure

SHOC2

is a scaffold protein composed of 20 leucine-rich repeat (LRR) domains that form a solenoid structure ^[1]. The leucine rich region forms a concave hydrophobic core which is necessary for binding with PP1C and MRAS. SHOC2 is the crucial mediator for SHOC2-PP1C-MRAS complex formation ^[1]. The leucine rich domain is very important in creating selectivity for the PP1C protein, as that protein is used for so many other complex pathways ^[1]. The LRR domains are stabilized by an N-terminal flanking 𝝰-helix and a C-terminal helix-turn-helix ^[2]. Alongside the conserved leucine residues in the LRR domain, there is a group of conserved asparagine residues that creates a stabilizing “asparagine ladder” that is necessary for the LRR fold, giving the SHOC2 its concave structure ^[2].

SHOC2 is also capable of causing various forms of Rasopathies. A common one is caused by a mutation known as p.S2G ^[3]. This mutation causes the formation of an additional 14-carbon saturated fatty acid chain on the N-terminal glycine of SHOC2 ^[3]. This causes SHOC2 to become attached to the cell membrane, resulting in a prolonged dephosphorylation of RAF by PP1C ^[3]. With this abnormality, there is overexpression of the MAPK pathway and increased cell proliferation genes ^[3]

PP1C

MRAS

Key Ligand Interactions

Figure 3: Electrostatic illustration of the amphipathic binding pocket of the LPA₁ receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.

SHOC2 and PP1C

SHOC2 and MRAS

PP1C and MRAS

Signaling Pathway

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. ↑ ^{1.0 1.1 1.2 1.3 1.4 1.5 1.6} 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
2. ↑ ^{2.0 2.1} 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
3. ↑ ^{3.0 3.1 3.2 3.3} Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-69. doi: 10.1146/annurev-genom-091212-153523.

Proteopedia Resources

Category:Lysophosphatidic acid binding

Category:Lysophosphatidic acid

Butler University Proteopedia Pages

See also:

• Receptor
• Transmembrane (cell surface) receptors
• G protein-coupled receptors