ABCMdb

PMID: 15765539

Amaral MD
Processing of CFTR: traversing the cellular maze--how much CFTR needs to go through to avoid cystic fibrosis?
Pediatr Pulmonol. 2005 Jun;39(6):479-91., [PubMed]

Sentences

No. Mutations Sentence Comment

49 ABCC7 p.Ile539Thr ABCC7 p.Ile539Thr ABCC7 p.Gly550Glu Indeed, by replacing either glycineat position550 by aglutamic acid residue (G550E) or isoleucine 539 by threonine (I539T), in cis with F508del it is possible to rescue both its membrane localization and channel activity.28 Another study showed that removal from F508del-CFTR of sequence signals, called arginine-framed tripeptide (AFT)-sequences (responsible for the ER retention or retrieval of other ion channels),29 permits nascent F508del-CFTR to mature and generate functional ClÀ channels at the cell surface.30 There are four of these arginine (R) sequences in CFTR: one in the N-terminal cytoplasmic domain (R29), two in NBD1 (R516 and R555), and one in the R domain (R766). Login to comment 50 ABCC7 p.Arg555Lys ABCC7 p.Arg555Lys ABCC7 p.Arg516Lys ABCC7 p.Arg29Lys ABCC7 p.Arg766Lys Although the simultaneous substitution of all four arginines by lysine (K) residues (4RK: R29K þ R516K þ R555K þ R766K) causes F508del-CFTR to function about one-third as efficiently as wt-CFTR, individual R/K substitutions at some of these positions, i.e., R29K30 and R555K,31 were also described as restoring F508del-CFTR function. Login to comment 51 ABCC7 p.Ile539Thr ABCC7 p.Gly550Glu Whether these AFT motifs are just ER-retention signals or, like G550E and I539T, also act as intrinsic folding determinants remains to be fully clarified. Login to comment 52 ABCC7 p.Gly550Glu Interestingly, and shedding some light on the mechanism involved, both G550E and 4RK also rescue another NBD1 trafficking mutant that is buried in NBD1.32 The C terminus of CFTR, containing a binding motif for a number of proteins (discussed below), also constitutes an intrinsic factor influencing CFTR proteinstability. Login to comment