期刊论文详细信息
FEBS Letters
Reversible inactivation of AT2 angiotensin II receptor from cysteine–disulfide bond exchange
Karnik, Sadashiva S1  Saad, Yasser1  Feng, Ying-Hong1 
[1] Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, NB50, 9500 Euclid Avenue, Cleveland, OH 44195, USA
关键词: Angiotensin II;    AT2 receptor;    Disulfide bond;    Thiol potentiation;    Cys–disulfide exchange;    G-protein-coupled receptor;   
DOI  :  10.1016/S0014-5793(00)02141-4
学科分类:生物化学/生物物理
来源: John Wiley & Sons Ltd.
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【 摘 要 】

Dithiothreitol (DTT) treatment of angiotensin II (Ang II) type 2 (AT2) receptor potentiates ligand binding, but the underlying mechanism is not known. Two disulfide bonds proposed in the extracellular domain were examined in this report. Based on the analysis of ligand affinity of cysteine (Cys, C) to alanine (Ala, A) substitution mutants, we provide evidence that Cys35–Cys290 and Cys117–Cys195 disulfide bonds are formed in the wild-type AT2 receptor. Disruption of the highly conserved Cys117–Cys195 disulfide bond linking the second and third extracellular segments leads to inactivation of the receptor. The Cys35–Cys290 bond is highly sensitive to DTT. Its breakage results in an increased binding affinity for both Ang II and the AT2 receptor-specific antagonist PD123319. Surprisingly, in the single Cys mutants, C35A and C290A, a labile population of receptors is produced which can be re-folded to high-affinity state by DTT treatment. These results suggest that the free –SH group of Cys35 or Cys290 competes with the disulfide bond formation between Cys117 and Cys195. This Cys–disulfide bond exchange results in production of the inactive population of the mutant receptors through formation of a non-native disulfide bond.

【 授权许可】

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