tailieunhanh - Báo cáo khoa học: Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone

The primary cause of cystic fibrosis (CF), the most frequent fatal genetic disease in Caucasians, is deletion of phenylalanine at position 508 (F508del), located in the first nucleotide-binding domain (NBD1) of the CF transmembrane conductance regulator (CFTR) protein. | Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone Toby S. Scott-Ward1 2 and Margarida D. Amaral1 2 1 Universidade de Lisboa Faculdade de Ciencias de Lisboa BioFIG Centre for Biodiversity Functionaland integrative Genomics Portugal 2 Centro de Genetica Humana Instituto Nacionalde Saude Dr. Ricardo Jorge Lisboa Portugal Keywords CFTR-interacting proteins correctors mechanism of disease small molecules surface plasmon resonance Correspondence M. D. Amaral EMBL - European Molecular Biology Laboratory Meyerhofstrasse 1 69117 Heidelberg Germany Fax 49 6221 387 8306 Tel 49 6221 387 8199 E-mail mdamaral@ Received 3 August 2009 revised 29 September 2009 accepted 1 October 2009 doi The primary cause of cystic fibrosis CF the most frequent fatal genetic disease in Caucasians is deletion of phenylalanine at position 508 F508del located in the first nucleotide-binding domain NBD1 of the CF transmembrane conductance regulator CFTR protein. F508del-CFTR is recognized by the endoplasmic reticulum quality control ERQC which targets it for proteasomal degradation preventing this misfolded but partially functional Cl channel from reaching the cell membrane. We recently proposed that the ERQC proceeds along several checkpoints the first of which utilizing the chaperone heat shock cognate 70 Hsc70 is the major one directing F508del-CFTR for proteolysis. Therefore a detailed characterization of the interaction occurring between F508del-CFTR and Hsc70 is critical to clarify the mechanism that senses misfolded F508del-CFTR in vivo. Here we determined by surface plasmon resonance that a F508del-murine m NBD1 binds Hsc70 with higher affinity KD nM than wild-type wt mNBD1 nM b ATP and ADP dramatically reduce NBD1-Hsc70 binding c the F508del mutation increases by approximately six-fold the ATP concentration required

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