CFTR mutations altering CFTR fragmentation

Kendra Tosoni, Michelle Stobbart, Diane M Cassidy, Andrea Venerando, Mario A Pagano, Simao Luz, Margarida D Amaral, Karl Kunzelmann, Lorenzo A Pinna, Carlos Miguel Farinha, Anil Mehta (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    12 Citations (Scopus)


    Most cystic fibrosis (CF), results from deletion of a phenylalanine (F508) in the CF transmembrane-conductance regulator (CFTR, ABCC7) which causes ER-degradation of the mutant. Using stably CFTR-expressing BHK cell lines, we demonstrate that wild type- and F508delCFTR are cleaved into differently sized, N- and C-terminal bearing fragments, with each hemi-CFTR carrying its nearest nucleotide binding domain (NBD), reflecting differential cleavage through the central CFTR R-domain. Similar NBD1-bearing fragments are present in the natively expressing HBE epithelial cell line. We also observe multiple smaller fragments of different sizes in BHK cells, particularly after F508del-mutation (ladder pattern). Trapping wild type CFTR in the ER did not generate a F508del fragmentation fingerprint. Fragments change their size/pattern again post mutation at sites involved in CFTR's in vitro interaction with the pleiotropic protein kinase CK2 (S511A in NBD1). F508del- and S511A- mutation generate different fragmentation fingerprints that are each unlike wild type; yet both mutants generate a new N-terminal-bearing CFTR fragments that are not observed with other CK2-related mutations (S511D, S422A/D, T1471A/D). We conclude that F508delCFTR is not degraded completely and there exists a relationship between CFTR's fragmentation fingerprint and the CFTR sequence through putative CK2-interactive sites that lie near F508.
    Original languageEnglish
    Pages (from-to)295-305
    Number of pages11
    JournalBiochemical Journal
    Issue number1
    Publication statusPublished - 2013


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