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A single amino acid determines preference between phospholipids and reveals length restriction for activation of the S1P4 receptor.
Holdsworth, Gill; Osborne, Daniel A; Pham, TrucChi Thi; Fells, James I; Hutchinson, Gillian; Milligan, Graeme; Parrill, Abby L.
Afiliação
  • Holdsworth G; Department of NCE Biology, Celltech R&D Ltd., 216 Bath Road, Slough, Berks, SL1 4EN, U.K. gill.holdsworth@celltechgroup.com
BMC Biochem ; 5: 12, 2004 Aug 06.
Article em En | MEDLINE | ID: mdl-15298705
ABSTRACT

BACKGROUND:

Sphingosine-1-phosphate and lysophosphatidic acid (LPA) are ligands for two related families of G protein-coupled receptors, the S1P and LPA receptors, respectively. The lysophospholipid ligands of these receptors are structurally similar, however recognition of these lipids by these receptors is highly selective. A single residue present within the third transmembrane domain (TM) of S1P receptors is thought to determine ligand selectivity; replacement of the naturally occurring glutamic acid with glutamine (present at this position in the LPA receptors) has previously been shown to be sufficient to change the specificity of S1P1 from S1P to 181 LPA.

RESULTS:

We tested whether mutation of this "ligand selectivity" residue to glutamine could confer LPA-responsiveness to the related S1P receptor, S1P4. This mutation severely affected the response of S1P4 to S1P in a [35S]GTP gamma S binding assay, and imparted sensitivity to LPA species in the order 140 LPA > 160 LPA > 181 LPA. These results indicate a length restriction for activation of this receptor and demonstrate the utility of using LPA-responsive S1P receptor mutants to probe binding pocket length using readily available LPA species. Computational modelling of the interactions between these ligands and both wild type and mutant S1P4 receptors showed excellent agreement with experimental data, therefore confirming the fundamental role of this residue in ligand recognition by S1P receptors.

CONCLUSIONS:

Glutamic acid in the third transmembrane domain of the S1P receptors is a general selectivity switch regulating response to S1P over the closely related phospholipids, LPA. Mutation of this residue to glutamine confers LPA responsiveness with preference for short-chain species. The preference for short-chain LPA species indicates a length restriction different from the closely related S1P1 receptor.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esfingosina / Lisofosfolipídeos / Receptores de Lisoesfingolipídeo Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: BMC Biochem Assunto da revista: BIOQUIMICA Ano de publicação: 2004 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Esfingosina / Lisofosfolipídeos / Receptores de Lisoesfingolipídeo Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: BMC Biochem Assunto da revista: BIOQUIMICA Ano de publicação: 2004 Tipo de documento: Article País de afiliação: Reino Unido