Sandbox Reserved 1172

Introduction

Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a G-protein coupled receptor and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative lysophosphatidic acid (LPA), a signaling molecule that acts as a potent mitogen upon binding to one of the six receptors. ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.

Structure

The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.

Key Ligand Interactions

Three separate interactions an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.

Function

The LPA1 receptor has been found to initiate downstream signaling cascades with three Galpha(link) proteins that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth.

Disease Relevance

The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with PI3K, PKB, and ERK to induce a hypertrophic response in the heart in order to offset reduced heart contractions. Because of the mitogen signaling activity of LPA1, abnormal expression has been linked to tumor growth, survival, and migration.

Receptor Comparison

Sphingosine 1-Phosphate Receptor

Endocannabinoid Receptor 1

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.