Identification of a novel endoplasmic reticulum export motif within the eighth alpha-helical domain (alpha-H8) of the human prostacyclin receptor

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dc.contributor.author Donnellan, Peter D.
dc.contributor.author Kimbembe, Cisca C.
dc.contributor.author Reid, Helen M.
dc.contributor.author Kinsella, B. Therese
dc.date.accessioned 2011-09-22T14:07:41Z
dc.date.available 2011-09-22T14:07:41Z
dc.date.copyright 2011 Elsevier B.V. en
dc.date.issued 2011-04
dc.identifier.citation Biochimica et Biophysica Acta (BBA) - Biomembranes en
dc.identifier.issn 0005-2736
dc.identifier.uri http://hdl.handle.net/10197/3165
dc.description.abstract The human prostacyclin receptor (hIP) undergoes agonist-dependent trafficking involving a direct interaction with Rab11a GTPase. The region of interaction was localised to a 14 residue Rab11a binding domain (RBD) within the proximal carboxyl-terminal (C)-tail domain of the hIP, consisting of Val299 – Val307 within the eighth helical domain (alpha-H8) adjacent to the palmitoylated residues at Cys308 – Cys311. However, the factors determining the anterograde transport of the newly synthesised hIP from the endoplasmic reticulum (ER) to the plasma membrane (PM) have not been identified. The aim of the current study was to identify the major ER export motif(s) within the hIP initially by investigating the role of Lys residues in its maturation and processing. Through site-directed and Ala-scanning mutational studies in combination with analyses of protein expression and maturation, functional analyses of ligand binding, agonist-induced intracellular signalling and confocal image analyses, it was determined that Lys297, Arg302 and Lys304 located within alpha-H8 represent the critical determinants of a novel ER export motif of the hIP. Furthermore, while substitution of those critical residues significantly impaired maturation and processing of the hIP, replacement of the positively charged Lys with Arg residues, and vice versa, was functionally permissible. Hence, this study has identified a novel 8 residue ER export motif within the functionally important alpha-H8 of the hIP. This ER export motif, defined by ‘K/R(X)4K/R(X)K/R’, has a strict requirement for positively charged, basic Lys/Arg residues at the 1st, 6th and 8th positions and appears to be evolutionarily conserved within IP sequences from mouse to man. en
dc.description.sponsorship Science Foundation Ireland en
dc.description.sponsorship Health Research Board en
dc.format.extent 2468930 bytes
dc.format.mimetype application/pdf
dc.language.iso en en
dc.publisher Elsevier en
dc.relation.requires Biomolecular and Biomedical Science Research Collection en
dc.relation.requires Conway Institute Research Collection en
dc.rights This is the author’s version of a work that was accepted for publication in Biochimica Biophys Acta. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimica Biophys Acta (2011) DOI 10.1016/j.bbamem.2011.01.003. en
dc.subject Prostacyclin receptor en
dc.subject Alpha helix 8 en
dc.subject GPCR en
dc.subject Endoplasmic reticulum en
dc.subject Trafficking en
dc.subject Export en
dc.subject.lcsh G proteins en
dc.subject.lcsh Prostacyclin--Receptors en
dc.subject.lcsh Endoplasmic reticulum en
dc.subject.mesh Receptors, G-Protein-Coupled en
dc.subject.mesh Receptors, Epoprostenol en
dc.subject.mesh Protein Transport en
dc.subject.mesh Endoplasmic Reticulum en
dc.title Identification of a novel endoplasmic reticulum export motif within the eighth alpha-helical domain (alpha-H8) of the human prostacyclin receptor en
dc.title.alternative ER export motif in a-H8 of the prostacyclin receptor en
dc.type Journal Article en
dc.internal.availability Full text available en
dc.internal.webversions Publisher's version en
dc.internal.webversions http://dx.doi.org/10.1016/j.bbamem.2011.01.003 en
dc.status Peer reviewed en
dc.identifier.volume 1808 en
dc.identifier.issue 4 en
dc.identifier.startpage 1202 en
dc.identifier.endpage 1218 en
dc.identifier.doi 10.1016/j.bbamem.2011.01.003.
dc.neeo.contributor Donnellan|Peter D.|aut| en
dc.neeo.contributor Kimbembe|Cisca C.|aut| en
dc.neeo.contributor Reid|Helen M.|aut| en
dc.neeo.contributor Kinsella|B. Therese|aut| en
dc.description.admin ot,ke,-SB02/09/2011 en


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