Titelaufnahme

Titel
Rescue of A1-adenosine receptor mutants by pharmacochaperoning / presented by Laura Málaga Diéguez
Verfasser / VerfasserinMálaga Diéguez, Laura
Begutachter / BegutachterinNanoff, Christian
Erschienen2009
UmfangVI, 135 Bl. : Ill., graph. Darst.
HochschulschriftWien, Med. Univ., Diss., 2009
Anmerkung
Zsfassung in dt. Sprache
SpracheEnglisch
Bibl. ReferenzOeBB
DokumenttypDissertation
Schlagwörter (DE)Adenosin / Rezeptor / GPCR / signaltransduktion
Schlagwörter (EN)Adenosine / Receptor / GPCR / pharmacochaperone
URNurn:nbn:at:at-ubmuw:1-8522 Persistent Identifier (URN)
Zugriffsbeschränkung
 Das Werk ist frei verfügbar
Dateien
Rescue of A1-adenosine receptor mutants by pharmacochaperoning [6.51 mb]
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Zusammenfassung (Englisch)

The carboxyl terminus that is the carboxyterminal tail (c-tail) of G protein-coupled receptors is divergent in length and structure and may represent an individualized cytoplasmic domain. In addition, in concerted action together with additional intracellular portions of the receptor, the carboxyl terminus participates in transmitting the signal from the ligand-binding pocket to the cognate G-protein(s).

Analysis of the crystal structure of rhodopsin, the G-protein-coupled receptor of the visual system, confirmed the presence of 7 transmembrane (TM) helices and revealed the existence of an 8th helix (helix 8) that projects at a right angle from the c terminus of TM7 (1). Based on the wealth of knowledge in the structure-activity relationship of rhodopsin, a hypothetical model was constructed for the A1-adenosine receptor (A1AR), a Gi/Go coupled receptor, which belongs to the rhodopsin subfamily of GPCRs.

The current thesis tests several predictions of this model; it focuses in particular on the hypothetical helix 8 of the the A1-adenosine receptor and posits that (i) the peripheral c-tail exerts an autoinhibitory restraint, which decreases agonist-mediated G protein activation; (ii) that the restrained receptor action is contingent upon the structure of the proximal portion of the c-tail which is due at least in part to an interaction between the tyrosine in the conserved motif NPXXY present in the 7th transmembrane domain and a phenylalanine in helix 8; (iii) that the tyrosine-phenylalanine interaction stabilizes the structure of the receptor and thus is relevant to the folding reaction in the ER and, as a corollary, for ER-export of the receptor protein.

This project (i) tests the structural model using both truncated versions and replacement of amino acids within the conserved NPXXY(X)6F microdomain. It also (ii) elucidates the site and molecular mechanism of the intracellular retention of mutant receptor constructs and (ii) explores the ability of receptor ligands to act as pharmacological chaperones, i.e rescuing surface expression of the constructs that fail cellular export.