ABCMdb

ABCC7 p.Pro205Gly

ClinVar:	c.614C>G , p.Pro205Arg ? , not provided c.613C>T , p.Pro205Ser D , Pathogenic
CF databases:	c.613C>T , p.Pro205Ser D , CF-causing ; CFTR1: This mutation was detected by SSCP analysism followed by direct sequencing. Mutation P205S was found in 3/270 unrelated Spanish CF non-[delta]F508 chromosomes. P205S is associated with haplotype 16/44/13. c.614C>G , p.Pro205Arg (CFTR1) D , c.614C>T , p.Pro205Leu (CFTR1) ? ,
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), Q: D (95%), R: D (95%), S: N (53%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] A protein sequence that can encode native structur... Nat Struct Biol. 2002 May;9(5):381-8. Wigley WC, Corboy MJ, Cutler TD, Thibodeau PH, Oldan J, Lee MG, Rizo J, Hunt JF, Thomas PJ
A protein sequence that can encode native structure by disfavoring alternate conformations.
Nat Struct Biol. 2002 May;9(5):381-8., [PMID:11938353]

Abstract [show]
The linear sequence of amino acids contains all the necessary information for a protein to fold into its unique three-dimensional structure. Native protein sequences are known to accomplish this by promoting the formation of stable, kinetically accessible structures. Here we describe a Pro residue in the center of the third transmembrane helix of the cystic fibrosis transmembrane conductance regulator that promotes folding by a distinct mechanism: disfavoring the formation of a misfolded structure. The generality of this mechanism is supported by genome-wide transmembrane sequence analyses. Furthermore, the results provide an explanation for the increased frequency of Pro residues in transmembrane alpha-helices. Incorporation by nature of such 'negative folding determinants', aimed at preventing the formation of off-pathway structures, represents an additional mechanism by which folding information is encoded within the evolved sequences of proteins.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
41 This alternate conformation is apparently not induced specifically by the Ser residue, because the control peptides (P205G, P205A and P205L) each assume a similar non-native structure under these conditions. Login to comment
49 CD spec- troscopy30 evaluated the seconday structure of peptides representing wild type m3, the CF-causing mutant P205S, and control peptides P205G, P205A and P205L solubilized in either micellar SDS (0.5% (w/v) SDS and 5mM phosphate buffer, pH 7.2) or polyfluorinated organic solvents (10% HFIP, 40% TFE and 50% (v/v) H2O). Login to comment
50 The lines used to represent each peptide are wild type m3, dashed red; P205S, dashed blue; P205G, solid green; P205A, solid light purple; and P205L, solid black. Login to comment

[hide] Contribution of proline residues in the membrane-s... J Biol Chem. 1996 Jun 21;271(25):14995-5001. Sheppard DN, Travis SM, Ishihara H, Welsh MJ
Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function.
J Biol Chem. 1996 Jun 21;271(25):14995-5001., [PMID:8663008]

Abstract [show]
Proline residues located in membrane-spanning domains of transport proteins are thought to play an important structural role. In the cystic fibrosis transmembrane conductance regulator (CFTR), the predicted transmembrane segments contain four prolines: Pro99, Pro205, Pro324, and Pro1021. These residues are conserved across species, and mutations of two (P99L and P205S) are associated with cystic fibrosis. To evaluate the contribution of these prolines to CFTR Cl- channel function, we mutated each residue individually to either alanine or glycine or mutated all four simultaneously to alanine (P-Quad-A). We also constructed the two cystic fibrosis-associated mutations. cAMP agonists stimulated whole cell Cl- currents in HeLa cells expressing the individual constructs that resembled those produced by wild-type CFTR. However, the amount of current was decreased in the rank order: wild-type CFTR = Pro324 > Pro1021 > Pro99 >/= Pro205 mutants. The anion selectivity sequence of the mutants (Br- >/= Cl- > I-) resembled wild-type except for P99L (Br- >/= Cl- = I-). Although the Pro99, Pro324, and Pro1021 mutants produced mature protein, the amount of mature protein was much reduced with the Pro205 mutants, and the P-Quad-A made none. Because the Pro99 constructs produced mature protein but had altered whole cell currents, we investigated their single-channel properties. Mutant channels were regulated like wild-type CFTR; however, single-channel conductance was decreased in the rank order: wild-type CFTR >/= P99G > P99L >/= P99A. These results suggest that proline residues in the transmembrane segments are important for CFTR function, Pro205 is critical for correct protein processing, and Pro99 may contribute either directly or indirectly to the Cl- channel pore.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
122 Mutant n Px/PCl Gx/GCl Br- Cl- IBr- ClI- CFTR 5 1.18 Ϯ 0.08 1.00 0.73 Ϯ 0.05 1.27 Ϯ 0.16 1.00 0.61 Ϯ 0.08 P99A 7 0.98 Ϯ 0.03 1.00 0.70 Ϯ 0.06 1.04 Ϯ 0.05 1.00 0.72 Ϯ 0.05 P99G 5 1.06 Ϯ 0.02 1.00 0.75 Ϯ 0.08 1.04 Ϯ 0.07 1.00 0.66 Ϯ 0.05 P99L 5 1.21 Ϯ 0.07 1.00 1.06 Ϯ 0.07 1.33 Ϯ 0.11 1.00 0.95 Ϯ 0.08 P205A 4 1.09 Ϯ 0.07 1.00 0.64 Ϯ 0.09 0.95 Ϯ 0.04 1.00 0.46 Ϯ 0.11 P205G 5 1.09 Ϯ 0.05 1.00 0.45 Ϯ 0.05 1.05 Ϯ 0.03 1.00 0.44 Ϯ 0.06 P205S 2 1.01 Ϯ 0.01 1.00 0.55 Ϯ 0.28 1.09 Ϯ 0.09 1.00 0.59 Ϯ 0.08 P324A 7 1.08 Ϯ 0.04 1.00 0.72 Ϯ 0.06 1.15 Ϯ 0.07 1.00 0.60 Ϯ 0.08 P324G 6 1.12 Ϯ 0.07 1.00 0.69 Ϯ 0.04 1.22 Ϯ 0.14 1.00 0.57 Ϯ 0.04 P1021A 3 1.15 Ϯ 0.17 1.00 0.73 Ϯ 0.11 1.17 Ϯ 0.10 1.00 0.47 Ϯ 0.19 P1021G 7 1.17 Ϯ 0.06 1.00 0.78 Ϯ 0.02 1.21 Ϯ 0.08 1.00 0.59 Ϯ 0.06 though for P99G the reduction was small, for P99A and P99L the effect was marked. Login to comment
126 The conductance for P99G was 7.31 Ϯ 0.24 pS (n ϭ 5), not significantly different from wild type (p ϭ 0.26). Login to comment
145 The number of cells responding to cAMP agonists with Cl- current activation relative to the total number of cells tested for each construct was: CFTR (8/16; 50%), P99A (11/12; 92%), P99G (9/19; 47%), P99L (10/19; 53%), P205A (7/12; 58%), P205G (5/9; 56%), P205S (7/20; 35%), P324A (9/18; 50%), P324G (9/22; 41%), P1021A (8/18; 44%), and P1021G (7/16; 44%). Login to comment
149 The number of cells responding to cAMP agonists with Cl2 current activation relative to the total number of cells tested for each construct was: CFTR (8/16; 50%), P99A (11/12; 92%), P99G (9/19; 47%), P99L (10/19; 53%), P205A (7/12; 58%), P205G (5/9; 56%), P205S (7/20; 35%), P324A (9/18; 50%), P324G (9/22; 41%), P1021A (8/18; 44%), and P1021G (7/16; 44%). Login to comment