ABCMdb

PMID: 18193900

Cheung JC, Deber CM
Misfolding of the cystic fibrosis transmembrane conductance regulator and disease.
Biochemistry. 2008 Feb 12;47(6):1465-73. Epub 2008 Jan 15., 2008-02-12 [PubMed]

Sentences

No. Mutations Sentence Comment

89 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp In contrast, the mutant G551D (also located in NBD1) affects mainly the function of CFTR but not its trafficking (71), while the mutant G1349D, at an equivalent position in NBD2 as G551 in NBD1, similarly affects the function of CFTR (72). Login to comment 90 ABCC7 p.Leu1065Pro ABCC7 p.Met1101Lys ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.His1085Arg ABCC7 p.Phe1052Val ABCC7 p.Leu1077Pro ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg ABCC7 p.Trp1098Arg ABCC7 p.Ala1067Thr ABCC7 p.His1054Asp ABCC7 p.Gly1061Arg ABCC7 p.Gln1071Pro In some additional examples, a number of mutations found in the fourth intracellular loop (H1054D, G1061R, L1065P, R1066C/H/L, Q1071P, L1077P, H1085R, W1098R, M1101K/ R) also affect the biosynthetic processing of CFTR (although function was not tested) (73); some intracellular loop 4 mutants (F1052V, K1060T, A1067T, G1069R, R1070Q/W) can process CFTR to the complex-glycosylated ("Band C") form but have altered channel activity compared to wild type. Login to comment 91 ABCC7 p.Arg334Trp ABCC7 p.Arg347His Mutants R334W, R347H/P also cause changes in ion conduction or regulation (74, 75). Login to comment 92 ABCC7 p.Pro67Ser The P67S mutation was FIGURE 3: The six "helical hairpins" and inclusive extracellular loops derived from the two portions (TMD1 and TMD2) of the transmembrane domain of wild type CFTR. Login to comment 99 ABCC7 p.Arg31Leu As further examples, the N-terminal mutations R31L/C produce CFTR molecules that are processed to Band C but have increased rates of endocytosis (77), while C-terminal truncation mutants can process to complex N-glycosylated forms but are subject to premature proteolysis by the proteasome (78). Login to comment 115 ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Leu346Pro ABCC7 p.Leu346Pro ABCC7 p.Arg347Ile WT, L346P, R347P, L346P/R347I, and R347H CFTR expression was assayed by immunoblotting, using the mouse monoclonal anti-HA Ab. Equal loading of proteins was verified by visualizing the Na+/K+-ATPase (lower panel). Login to comment 121 ABCC7 p.Val232Asp V232D is the CF-phenotypic mutant in TM4. Login to comment 135 ABCC7 p.Arg347Pro ABCC7 p.Leu346Pro ABCC7 p.Leu346Pro We therefore examined two CF-phenotypic missense mutations in the CFTR channel pore [L346P and R347P in TM6] that involve gain of a Pro residue, but where only the nonconservative mutation L346P represents a significant loss of segment hydropathy. Login to comment 137 ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Leu346Pro When the biogenesis of corresponding full-length CFTR mutants was examined in this context, the protein harboring the L346P mutation was found to be unstable, while the wild type, R347P, along with the R347H mutant protein, processed normally (Figure 4A). Login to comment 138 ABCC7 p.Leu346Pro ABCC7 p.Arg347Ile The defect could be rescued in part by restoring hydrophobicity to TM6 via the double mutant L346P/R347I (Figure 4B). Login to comment 141 ABCC7 p.Val232Asp We addressed the possibility experimentally that wild type Q207 in TM3 can form an interhelical side chain-side chain H-bond with CF-phenotypic mutant V232D in TM4 in an investigation of a series of helix-loop-helix ("hairpin") constructs derived from CFTR TM helices 3 and 4. Login to comment 145 ABCC7 p.Glu217Gly ABCC7 p.Gln220Arg When we examined the potential structural impact of CF-phenotypic mutations in extracellular loop 2 (ECL2) (including E217G and Q220R) in a library of wild type and mutant TM3-ECL2- TM4 hairpin constructs, we found that SDS-PAGE gel migration rates differed over a range of nearly 40% +/- the wild type position, and that decreased migration rates FIGURE 6: Disruption of helix-helix interactions by increased R-helical structure in the extracellular loop. Login to comment