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Human Lysophosphatidic Acid Receptor 1

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Lysophosphatidic Acid

Figure 1: Chemical Structure of LPA (monoacyl-sn-glycero-3-phosphate)

Lysophosphatidic Acid (LPA) consists of an unsaturated fatty acid chain, a glycerol backbone, and a free phosphate group (Figure 1). Lysophosphatidic acid is found in nearly all cells, tissues, and fluids of the body. LPA is present intracellularly as a precursor of phospholipid biosynthesis, and extracellularly as a signalling phospholipid. This page will focus on the signalling role of LPA.

Extracellularly, LPA is produced from lysophosphatidylcholine by the enzyme autotaxin. Autotaxin was originally linked with metastasis, and this link was later discovered to be mediated through the production of LPA, which signals cell proliferation.^[3] All of LPA’s activities are receptor mediated; the signalling lipid interacts with at least six G-protein coupled receptors LPA₁-LPA₆.

Function

Of the six LPA G-protein coupled receptors, LPA₁ is the most widely expressed. Lysophosphatidic acid receptor 1 is coupled to a heterotrimeric G protein. The three G alpha proteins that LPA₁ couples to are G_i, G_q, and G_12/13.^[4] From these three G proteins many signal transduction pathways are activated (Figure 2). The downstream effects of G_i are cell proliferation, cell survival, cell migration, and morphological changes. G_q signals the inhibition of gap-junctional communication. Those of G_12/13 are morphological changes, inhibition / reversal of differentiation, contraction, and increased endothelial permeability. These downstream functions show the wide array of effects that LPA can have on the body. Targeted deletion of LPA receptors has had an effect on every organ system examined.^[5]

LPA₁ is part of the larger EDG (endothelial differentiation gene) family which includes the sphingosine 1-phosphate receptors. Compare to S1P…

Structure

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Structure of LPA1 1.1 Structural Stabilization 1.2 Binding Pocket 1.3 Comparison to S1P Structure of LPA1 The LPA1 receptor consists of seven transmembrane alpha helices. There are more (red) resides on the intercellular and extracellular areas of the receptor, while most residues positioned inside the membrane are hydrophobic (blue). The receptor lies in the membrane as shown in Figure 3, and as shown by the bound to it in orange. Image:LPA in membrane.fw.png Figure 3: LPA in membrane Structural Stabilization There are many different stabilizing factors in the structure of this receptor. There are three native disulfide bonds in the extracellular region. One of these bonds constrains the N terminal helix to extracellular loop 2. The functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. It also provides that interact with the ligand when bound. Binding Pocket The for LPA inside the receptor consists of both polar and nonpolar residues. There are polar residues on the N terminus and along one side of the binding pocket. There is also a large hydrophobic pocket for the long acyl chain of LPA. Comparison to S1P Lysophosphatidic Acid Receptors (LPA) are part of a larger family known as lysophospholipid receptor family (EDG family). As previously mentioned, this family also includes the sphingosine-1-phosphate receptors. The structure for S1P1 is known, so it is used as a reference to compare to the structure of LPA1. [5] There is a difference in binding paths between these two receptors. The binding path in the LPA1 is located in the extracellular milieu. While in the S1P1 the ligands are able to have access to the membrane so that the binding can occur. Figure 3: Comparison of the binding pockets of LPA1 and S1P1 receptors There is a difference in the shape of the electron density from the binding pocket. In S1P1 the binding pocket has more of an oval shape. For the LPA1 receptor the binding pocket has a spherical shape. Since the binding pocket is more spherical it gives LPA1 the ability to be able to recognize a larger group of chemical species. In particular the ability to bind with acyl chains of varying lengths [5].

Clinical Relevance

Cancer

Fibrosis

Pain

Endocannabinoids

The endocannabinoid system, located in the mammalian nervous system, regulates a variety of physiological processes including appetite, pain sensation, mood, and memory. Endocannabinoids, the natural ligands for cannabinoid receptors, are similar in structure to lysophosphatidic acid. Both the cannabinoid receptors and the LPA receptors have a preference for long unsaturated acyl chains.

References

1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
3. ↑ Boutin JA, Ferry G. Autotaxin. Cell Mol Life Sci. 2009 Sep;66(18):3009-21. doi: 10.1007/s00018-009-0056-9. Epub , 2009 Jun 9. PMID:19506801 doi:http://dx.doi.org/10.1007/s00018-009-0056-9
4. ↑ Moolenaar WH, van Meeteren LA, Giepmans BN. The ins and outs of lysophosphatidic acid signaling. Bioessays. 2004 Aug;26(8):870-81. PMID:15273989 doi:http://dx.doi.org/10.1002/bies.20081
5. ↑ ^{5.0 5.1 5.2} Chrencik JE, Roth CB, Terakado M, Kurata H, Omi R, Kihara Y, Warshaviak D, Nakade S, Asmar-Rovira G, Mileni M, Mizuno H, Griffith MT, Rodgers C, Han GW, Velasquez J, Chun J, Stevens RC, Hanson MA. Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. Cell. 2015 Jun 18;161(7):1633-43. doi: 10.1016/j.cell.2015.06.002. PMID:26091040 doi:http://dx.doi.org/10.1016/j.cell.2015.06.002