细胞内谷胱甘肽可挽救靶向错误的MRPdeltaF728突变体。

Mistargeted MRPdeltaF728 mutant is rescued by intracellular GSH.

作者信息

Buyse Frédéric, Vandenbranden Michel, Ruysschaert Jean-Marie

机构信息

Structure et Fonction des Membranes Biologiques (S.F.M.B.), Centre de Biologie Structurale et de Bioinformatique, Université Libre de Bruxelles, CP 206/2, Bd. du Triomphe, B-1050 Brussels, Belgium.

出版信息

FEBS Lett. 2004 Dec 3;578(1-2):145-51. doi: 10.1016/j.febslet.2004.10.089.

DOI:10.1016/j.febslet.2004.10.089

PMID:15581632

Abstract

The most common cystic fibrosis-causing mutation is the deletion of the widely conserved phenylalanine 508 (DeltaF508) of CFTR. The mutant is unable to fold correctly and to transit to the plasma membrane. MRP1 belongs to the same subfamily of ABC proteins as CFTR and confers resistance to a wide range of chemotherapeutic drugs. By analogy, phenylalanine 728 was deleted in MRP1. Our results shown that MRPDeltaF728 is correctly targeted to the plasma membrane, actively transports doxorubicin (DOX) and vincristine (VCR) and shares a structure identical to MRP1. Intracellular GSH depletion however results in a mistargeted mutant that is retained into the cytoplasm, while in the same conditions wild-type MRP1 is correctly routed to the plasma membrane. The GSH-protein complex could adopt a stable conformation protected against proteolytic degradation and correctly targeted to the plasma membrane.

摘要

最常见的导致囊性纤维化的突变是囊性纤维化跨膜传导调节因子（CFTR）广泛保守的苯丙氨酸508缺失（ΔF508）。该突变体无法正确折叠并转运至质膜。多药耐药相关蛋白1（MRP1）与CFTR属于ABC蛋白的同一家族，并赋予对多种化疗药物的抗性。以此类推，在MRP1中删除了苯丙氨酸728。我们的结果表明，MRPΔF728能正确定位于质膜，能主动转运阿霉素（DOX）和长春新碱（VCR），并且与MRP1具有相同的结构。然而，细胞内谷胱甘肽（GSH）耗竭会导致突变体定位错误并滞留在细胞质中，而在相同条件下野生型MRP1能正确转运至质膜。GSH-蛋白质复合物可能会形成一种稳定的构象，免受蛋白水解降解，并能正确定位于质膜。