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J. Biol. Chem., Vol. 276, Issue 52, 49213-49220, December 28, 2001
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From the 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
LPA3/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.
A Single Amino Acid Determines Lysophospholipid Specificity
of the S1P1 (EDG1) and LPA1 (EDG2) Phospholipid
Growth Factor Receptors*
§,§,
,**,, and§§
Department of Physiology, University of
Tennessee Health Sciences Center Memphis, Memphis, Tennessee 38163 and the ¶ Department of Chemistry and Computational Research on
Materials Institute, The University of Memphis, Memphis, Tennessee
38152
*
This work was funded in part by grants from the American
Heart Association and Grants HL61469 and CA92160 from the National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept. of Chemistry, Eastern Kentucky
University, Richmond, KY 40475-3102.
**
Present address: Inst. of Enzymology, Hungarian Academy of
Sciences, Budapest, P.O. Box 7, H-1518, Hungary.
Senior co-authors.
§§
To whom correspondence should be addressed. Tel.: 901-678-2638;
Fax: 901-678-3447; E-mail: aparrill@memphis.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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