A Single Amino Acid Determines Lysophospholipid Specificity of the S1P 1 (EDG1) and LPA1 (EDG2) Phospholipid Growth Factor Receptors

De An Wang, Zsolt Lorincz, Debra L. Bautista, K. Liliom, Gabor Tigyi, Abby L. Parrill

Research output: Contribution to journalArticle

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Abstract

The phospholipid growth factors sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are ligands for the related G protein-coupled receptors S1P1/EDG1 and LPA1/EDG2, respectively. We have developed a model of LPA1 that predicts interactions between three polar residues and LPA. One of these, glutamine 125, which is conserved in the LPA receptor subfamily (LPA1/EDG2, LPA2/EDG4, and LPA 3/EDG7), hydrogen bonds with the LPA hydroxyl group. Our previous S1P1 study identified that the corresponding glutamate residue, conserved in all S1P receptors, ion pairs with the S1P ammonium. These two results predict that this residue might influence ligand recognition and specificity. Characterization of glutamate/glutamine interchange point mutants of S1P1 and LPA1 validated this prediction as the presence of glutamate was required for S1P recognition, whereas LPA recognition was possible with either glutamine or glutamate. The most likely explanation for this dual specificity behavior is a shift in the equilibrium between the acid and conjugate base forms of glutamic acid due to other amino acids surrounding that position in LPA1, producing a mixture of receptors including those having an anionic glutamate that recognize S1P and others with a neutral glutamic acid that recognize LPA. Thus, computational modeling of these receptors provided valid information necessary for understanding the molecular pharmacology of these receptors.

Original languageEnglish
Pages (from-to)49213-49220
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number52
DOIs
Publication statusPublished - Dec 28 2001

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Lysophospholipids
Growth Factor Receptors
Glutamic Acid
Phospholipids
Amino Acids
Glutamine
Lysophosphatidic Acid Receptors
Lysosphingolipid Receptors
Ligands
Interchanges
G-Protein-Coupled Receptors
sphingosine 1-phosphate
Ammonium Compounds
Hydroxyl Radical
lysophosphatidic acid
Hydrogen
Intercellular Signaling Peptides and Proteins
Hydrogen bonds
Pharmacology
Ions

ASJC Scopus subject areas

  • Biochemistry

Cite this

A Single Amino Acid Determines Lysophospholipid Specificity of the S1P 1 (EDG1) and LPA1 (EDG2) Phospholipid Growth Factor Receptors. / Wang, De An; Lorincz, Zsolt; Bautista, Debra L.; Liliom, K.; Tigyi, Gabor; Parrill, Abby L.

In: Journal of Biological Chemistry, Vol. 276, No. 52, 28.12.2001, p. 49213-49220.

Research output: Contribution to journalArticle

Wang, De An ; Lorincz, Zsolt ; Bautista, Debra L. ; Liliom, K. ; Tigyi, Gabor ; Parrill, Abby L. / A Single Amino Acid Determines Lysophospholipid Specificity of the S1P 1 (EDG1) and LPA1 (EDG2) Phospholipid Growth Factor Receptors. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 52. pp. 49213-49220.
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