ABCMdb

PMID: 23248597

Kim SJ, Skach WR
Mechanisms of CFTR Folding at the Endoplasmic Reticulum.
Front Pharmacol. 2012 Dec 13;3:201. doi: 10.3389/fphar.2012.00201. eCollection 2012., [PubMed]

Sentences

No. Mutations Sentence Comment

66 ABCC7 p.Gly85Glu ABCC7 p.Gly91Arg An important implication of this topogenesis mechanism is highlighted by two CF-causing mutations, G85E and G91R, each of which introduces an additional ionizable residue into TM1. Login to comment 68 ABCC7 p.Gly85Glu ABCC7 p.Gly91Arg Despite achieving correct topology, however, G85E and G91R still disrupt CFTR folding and trafficking (Xiong et al., 1997; Patrick et al., 2011). Login to comment 96 ABCC7 p.Thr908Asn The CF mutation T908N, however, creates a glycosylation site that is recognized by OST even though it is only four-residues from the predicted N-terminus of TM8. Login to comment 100 ABCC7 p.Asp924Val Interestingly, removal of an aspartate residue from TM8 (D924V) prevents transient lumenal exposure and at the same time confers independent stop transfer activity. Login to comment 110 ABCC7 p.Lys95Ala ABCC7 p.Glu92Ala For example, replacement of ionizable residues in TM1 (E92A and K95A) converts TM1 to a strong signal anchor sequence, thus favoring cotranslational topogenesis, but disrupts CFTR function (Lu et al., 1998; Patrick et al., 2011). Login to comment 111 ABCC7 p.Asp924Val Similarly, the D924V mutation converts TM8 to a strong strop transfer sequence and facilitates cotranslational membrane integration, but decreases CFTR chloride conductance (our observations). Login to comment 122 ABCC7 p.Arg553Gln ABCC7 p.Ile539Thr ABCC7 p.Gly550Glu Mutations that increase NBD1 solubility and/or thermodynamic stability (I539T, G550E, R553Q, and others; Teem et al., 1993; DeCarvalho et al., 2002; Roxo-Rosa et al., 2006; Pissarra et al., 2008; Hoelen et al., 2010) and/or decrease backbone flexibility (Aleksandrov et al., 2012) can enhance both NBD1 folding yield in cells and trafficking efficiency of full length WT as well as ࢞F508 CFTR (Figure 3B). Login to comment