ABCMdb

ABCC7 p.Phe429Ser

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Publications

PMID: 16697012 [PubMed] Ramaen O et al: "Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site."

No. Sentence Comment

63 Structure based sequence alignment of MRP1-NBD1 with MRP1-NBD2, h-CFTR-NBD1 (pdb code 1xmi, F508A F429S H667R mutant), BtuCD (pdb code 1l7v), TAP1 (pdb code 1jj7), MJ0796 (pdb code 1l2t, E171Q mutant), MJ1267 (pdb code 1g9x, N31C mutant), HisP (pdb code 1b0u) and HlyB-NBD (pdb code 1mt0). Login to comment

PMID: 15528182 [PubMed] Lewis HA et al: "Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure."

No. Sentence Comment

82 Crystal Structure of hNBD1 Shows That Regulatory Protein Segments Adopt Multiple Conformations Altering Access to the Active Site-High-resolution diffraction data were obtained for hNBD1-2b-F508A, containing two solubilizing mutations (F429S and H667R) in addition to the F508A substitution (Table II). Login to comment
84 One (F429S) participates in intermolecular packing interactions stabilizing the lattice (data not shown). Login to comment
100 Crystal Structure of ⌬F508 hNBD1 Shows Minimal Conformational Changes but Substantive Changes in Surface Topography at the Putative Site of MSD1 Interaction-Crystals diffracting to a resolution of 2.3 Å were obtained for hNBD1-7a- ⌬F508, which contains seven mutations (F409L, F429S, F433L, G550E, R553Q, R555K, H667R) in addition to the deletion of Phe-508 (see Table II). Login to comment
138 Of the seven solubilizing mutations present in the ⌬F508 form of hNBD1, three (F409L, F429S, F433L) occur in disordered regions and therefore likely interact with solvent, whereas residue H667R is only minimally solvent-exposed on the surface of ␣-helix 9b in the RE. Login to comment

PMID: 15619636 [PubMed] Thibodeau PH et al: "Side chain and backbone contributions of Phe508 to CFTR folding."

No. Sentence Comment

148 Note added in proof: Crystal structures of the human F508A missense NBD1 (with solublizing mutations F429S and H667R) and the corrected ∆F508 NBD1 (with three known suppressor mutations G550E, R553Q and R555K, and the solublizing mutations F409L, F429S, F433L and H667R) have been reported51. Login to comment

PMID: 18597042 [PubMed] Mornon JP et al: "Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces."

No. Sentence Comment

97 These mutations are actually located outside the NBD1 structure core, in the regulatory insertion (F409L, F429S, F433L) and extension (R667H), or in the signature sequence region (G550E, R553Q, R555K), whose local conformations in the crystal structure and in our model are perfectly superimposable. Login to comment

PMID: 19176754 [PubMed] Du K et al: "Cooperative assembly and misfolding of CFTR domains in vivo."

No. Sentence Comment

155 The N1*⌬F and N1*4D contains the same mutations as defined in a. N1*3S incorporates the F429S, F494N, and Q637R solubilization mutations. Login to comment
174 Five, remarkably, introducing three solubilization mutations (F429S, F494N, and Q637R) that were required to produce soluble, recombinant NBD1 in bacteria (Lewis et al., 2005), significantly increased the steady-state cell surface expression of the CD4Tl-N1*-3S at 37°C and suppressed the expression defect at 26°C (Figure 3, b and c). Login to comment

PMID: 19781595 [PubMed] Bisignano P et al: "Molecular dynamics analysis of the wild type and dF508 mutant structures of the human CFTR-nucleotide binding domain 1."

No. Sentence Comment

20 Structures were obtained by X-ray crystallography, at a resolution of 2.55 Å and 2.30 Å for WT and mutant, respectively. These structures are both characterized by the presence of seven mutations: F409L, F429S, F433L, G550E, R553Q, R555K and H667R which make them more soluble and therefore more easily crystallizable [6,7]. Login to comment
152 The chosen PDB entries,1XMJ and 2BBO, contain seven mutations, F409L, F429S, F433L, G550E, R553Q, R555K and H667R, that were introduced to the NBD1, wild type and dF508 used for this study, to facilitate the crystallization of the polypeptide [6]. Login to comment
154 It is interesting to notice that several of these mutations (F429S, G550E, R555K), have been identified as ''rescue`` mutations [18-20], that improve the expression of the defective dF508 CFTR. Login to comment

PMID: 19927121 [PubMed] Kanelis V et al: "NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR."

No. Sentence Comment

107 Significant conformational changes, apart from differences in the local surface properties at the mutation site, were not observed in the crystal structures of DF508 NBD1-RE (also containing F429S, F494N, and Q637A mutations required for protein solubility and crystallization) (Lewis et al, 2004, 2005) and of DF508 NBD1 lacking the RI and the RE (PDB code 2PZF). Login to comment
249 The additional mutations (F494N, Q637A or F429S, F494N, and Q637R) in the DF508 NBD1-RE construct required for protein solubility and crystallization (Lewis et al, 2005) also partially rescue the trafficking and gating defects of full-length DF508 CFTR, suggesting that the crystal structure of DF508 NBD1-RE may correspond to a partially corrected conformation (Pissarra et al, 2008). Login to comment
250 It is noteworthy that the F429S mutation is in the RI and further promotes the revertant effect produced by the F494N/Q637 mutant (Pissarra et al, 2008). Login to comment

PMID: 19944699 [PubMed] Lewis HA et al: "Structure and dynamics of NBD1 from CFTR characterized using crystallography and hydrogen/deuterium exchange mass spectrometry."

No. Sentence Comment

48 These constructs have two solubilizing mutations selected because they are sequence variations naturally present in more soluble NBD1 variants from other vertebrate species [F494N in the γ- phosphate switch from several fish species (unpublished results) and Q637R in the RE from mouse].5,37 One newly reported ΔF508 structure has only these two mutations (PDB ID 2BBT, construct hNBD1-2f- ΔF508, Rwork =23.2 and Rfree =29.5 at 2.30 Å), while the other has an additional F429S mutation in a disordered region of the RI (PDB ID 2BBT, construct hNBD1-3-ΔF508, Rwork =22.6 and Rfree =29.1 at 2.05 Å). Login to comment
53 Therefore, the 2BBS and 2BBT structures permit assessment of the effects of these differences in solvent environment on hNBD1 conformation, because the only sequence difference between them is the F429S mutation in the disordered region of the RI. Login to comment
325 Not shown here are three residues that were mutated in various constructs but located in the disordered region of the RI (i.e., the F429S mutation present in constructs 2b, 3, and 7a and the F409L and F433L mutations present in construct 7a). Login to comment

PMID: 20150177 [PubMed] Atwell S et al: "Structures of a minimal human CFTR first nucleotide-binding domain as a monomer, head-to-tail homodimer, and pathogenic mutant."

No. Sentence Comment

65 Human NBD1 proteins utilized Clone name Sequencea 2935c469 Ser-NBD1[387-646(D405-436)] 2935c472 Ser-NBD1[387-646(D405-436,DF508)] 2935c492 Ser-NBD1[375-646(D405-436)] 2935c382b Ser-NBD1[389-678(F429S,F494N,Q637R)] 2935c371c Ser-NBD1[389-678(F429S,F494N,Q637R, DF508)] a All of the NBD1 proteins start with a non-native serine preceding the NBD1 sequence. Login to comment
114 Human NBD1 387-646(D405-436) is more stable and binds ATP tighter than non-truncated constructs Truncated and non-truncated NBD1 proteins were analyzed for their thermal unfolding properties: NBD1 387-646(D405-436) and NBD1 389-678[F429S,F494N,Q637R]. Login to comment
138 (B) The same analysis was conducted with NBD1[389-678(F429S,F494N,Q637R)] proteins (2935c382 and 2935c371). Login to comment
226 The 389-678(F409L, F429S, F433L, G550E, R553Q, R555K, H667R) (hNBD1-7a) structures are shown without (dark blue) and with the DF508 mutation (light blue) (H. Lewis, in preparation). Login to comment
249 Many of the solubilizing mutations developed for non-truncated NBD1 are in the RI or Q-loop cleft (F409L, F429S, F433L and F494N) and might function by reducing these interactions. Login to comment

PMID: 20551307 [PubMed] Da Paula AC et al: "Folding and rescue of a cystic fibrosis transmembrane conductance regulator trafficking mutant identified using human-murine chimeric proteins."

No. Sentence Comment

218 Single Channel Behavior of Processing Mutant K584E-CFTR-In previous research, we demonstrated that revertant (e.g. G550E-CFTR (24)) and solubilizing mutations (e.g. F429S/F494N/Q637R (13)) rescue defects in CFTR channel gating in addition to promoting the cell surface expression of F508del-CFTR. Login to comment

PMID: 20687133 [PubMed] Protasevich I et al: "Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1."

No. Sentence Comment

44 hNBD1 Nameb Termini / Mutationsc Tm d DTm ¼ Tm D508 - Tm wt ( C) PDB ID 1 hNBD1-D(RI,RE) 2935c46917 387-646[D405-436] 57.7 þ 0.2 2PZE 1 (F508del)hNBD1D (RI,RE) 2935c47217 387-646[D405-436, F508del] 51.5 þ 0.3 À6.2 þ 0.3 2PZF 2 387-646[D405-436, V510D] 60.2 þ 0.4 2 387-646[D405-436, V510D, F508del] 53.0 þ 0.1 À7.2 þ 0.4 3 387-646[D405-436, F494N, Q637R] 59.2 3 387-646[D405-436, F494N, Q637R, F508del] 52.8 À6.4 4 387-646[D405-436, G550E, R553Q, R555K] 61.7 4 387-646[D405-436, G550E, R553Q, R555K,F508del] 55.7 À6.0 5 387-678[D405-436] 58.1 5 387-678[D405-436, F508del] 51.7 À6.2 6 hNBDI-315 2935c38217 389-678[F429S, F494N, Q637R] 49.8 þ 0.3 6 hNBDI-3F508del15 2935c37117 389-678[F429S, F494N, Q637R, F508del] 43.6 þ 0.1 À6.3 þ 0.3 2BBS 7 389-678[F429S, F494N, L636E5, Q637R] 50.5 þ 0.2 7 389-678[F429S, F494N, L636E, Q637R, F508del] 44.9 À6.2 þ 0.2 a DSC conducted at 1 mg/mL protein. Login to comment

PMID: 20687163 [PubMed] Wang C et al: "Integrated biophysical studies implicate partial unfolding of NBD1 of CFTR in the molecular pathogenesis of F508del cystic fibrosis."

No. Sentence Comment

28 Surprisingly, several of these solubilizing surface mutations in hNBD1, identified in a screen focused exclusively on the in vitro solubility of hNBD1, were shown to suppress the in vivo trafficking defect of F508del-CFTR more strongly than the best existing pharmacological agents.32,38 Notably, the mutated residues (e.g., F429S, F494N, and Q637R) are not in direct contact with F508 and do not appear to be allosterically coupled.18 A similar hydrophobic-to-hydrophilic substitution in the immediate vicinity of F508, the V510D mutation, also strongly suppresses the in vivo trafficking defect of F508del-CFTR.39,40 It was proposed that these substitutions could block adventitious chaperone interactions that prevent proper ER export.18 However, there is as yet no concrete evidence explaining the tight correlation between the effects of mutations on the in vitro solubility properties of hNBD1 and the in vivo trafficking properties of human CFTR. Login to comment
118 Solubilizing surface mutations need to be introduced into full-length hNBD1 to obtain sufficient material for biophysical studies.15 Supporting Information Figure S5 compares the behavior of matched full-length and D(RI,RE) constructs containing F429S, F494N, and Q637R mutations15 in the absence or presence of the F508del mutation. Login to comment

PMID: 21594798 [PubMed] Kanelis V et al: "NMR spectroscopy to study the dynamics and interactions of CFTR."

No. Sentence Comment

136 Alternatively, the protein can be modified to increase solubility by specific point mutations (F494N and to a lesser degree F429S and Q637R) without deleting the RI (46). Login to comment
140 Higher concentrations of glycerol and lower temperatures further stabilize the protein, but increase the viscosity of the solution, leading to Table 25.1 List of preferred CFTR constructs for NMR studies Construct Boundaries "Solubilizing" mutations mNBD1-RE 389-673 G550E, R553M, R555K hNBD1a 387-404, 437-646 None hNBD1-REa 387-404, 437-678 None hNBD1-RE 389-678 F494N hNBD1-RE 389-678 F429S, F494N, Q637R aThe RI (residues 405-436) have been deleted in these constructs. Login to comment

PMID: 22265408 [PubMed] Rabeh WM et al: "Correction of both NBD1 energetics and domain interface is required to restore DeltaF508 CFTR folding and function."

No. Sentence Comment

26 Both the R mutations (G550E, R553Q, and R555K) and S mutations (F409L, F429S, F433L, F494N, and H667R) could partially rescue the DF508 CFTR folding and functional defect (Lewis et al., 2005; Pissarra et al., 2008; Teem et al., 1993, 1996) and were assumed to stabilize the domain either alone or in combinations (1S, 3S, R, R1S, and R4S; see Figure 1B). Login to comment

PMID: 18417076 [PubMed] Cheung JC et al: "Molecular basis for the ATPase activity of CFTR."

No. Sentence Comment

107 The construct generated had several mutations to increase solubility of the domain (F409L, F429S, F433L, G550E, R553Q, R555K, H667R) in addition to the deletion of F508. Login to comment

PMID: 18215773 [PubMed] Pissarra LS et al: "Solubilizing mutations used to crystallize one CFTR domain attenuate the trafficking and channel defects caused by the major cystic fibrosis mutation."

No. Sentence Comment

5 Although F508del-NBD1 shows only minor conformational changes relative to that of wild-type NBD1, additional mutations (F494N/Q637R or F429S/F494N/Q637R) were required for domain solubility and crystallization. Login to comment
33 However, these new F508del-NBD1 crystal structures still required either two (F494N/Q637R; Protein Data Bank [PDB] ID code: 2BBT) or three (F429S/F494N/ Q637R; PDB ID code: 2BBS) additional mutations for domain solubility and, hence, crystal formation (Lewis, 2005). Login to comment
35 To test these ideas, we investigated the effects of the mutations F494N/Q637R and F429S/F494N/Q637R on wt- and F508del-CFTR by studying: (1) the in vivo folding yield of NBD1, (2) the processing and trafficking of the full-length CFTR protein, and (3) the ClÀ channel function of CFTR. Login to comment
37 RESULTS While studying the effects of F508del on the structure of NBD1 from CFTR, Lewis (2005) introduced the mutations F494N/ Q637R (double; D) and F429S/F494N/Q637R (triple; T) into NBD1 to improve domain solubility and crystallization. Login to comment
42 Solubilizing Mutations Improve wt- and F508del-NBD1 Yield To explore whether F429S, F494N, and Q637R improve the yield of soluble NBD1, wt-NBD1 and F508del-NBD1 were expressed in bacterial cells in the absence and presence of the solubilizing mutations. Login to comment
144 Structural Implications An interesting aspect of the action of the solubilizing mutations (double, F494N/Q637R; triple, F429S/F494N/Q637R) is their remote location from that of F508. Login to comment
152 The third solubilizing mutation, F429S, further promotes the revertant effect produced by the double mutant (F494N/Q637R) on F508del-CFTR, as the triple mutant (F429S/F494N/Q637R) visibly increased maturation of F508del-CFTR as measured by the higher maturation yield at steady state of F508delT-CFTR compared with that of F508delD-CFTR (Figure 1C). Login to comment
154 This suggests that F429S might lie on the surface of NBD1 in a position where it likely interacts with the environment (Lewis et al., 2004, 2005). Login to comment
175 The available crystal structure of F508del-NBD1 was determined after the introduction of additional mutations (F494N/Q637R or F429S/ F494N/Q637R) to help domain solubilization and crystal formation. Login to comment
182 Site-Directed Mutagenesis, Cells, and CFTR Expression To introduce the solubilizing mutations F494N/Q637R and F429S/F494N/ Q637R into wt- and F508del-CFTR cDNAs in the pNUT expression vector, we used the primers F429S, 50 -GGTGATGACAGCCTCTCCTTCAGTAATTTC TCA-30 ; F494N, 50 -CATTCTGTTCTCAGAATTCCTGGATTATGCCTGG-30 ; Q637R, 50 -GAACTCCAAAATCTAAGGCCAGACTTTAGCTC-30 and the QuikChange site-directed mutagenesis kit (Stratagene). Login to comment
187 Cell lines expressing different solubilizing mutations are referred to as follows: wtD-CFTR, F494N-Q637R-CFTR; F508delD-CFTR, F494N- F508del-Q637R-CFTR; wtT-CFTR, F429S-F494N-Q637R-CFTR; and F508delT-CFTR, F429S-F494N-F508del-Q637R-CFTR. Login to comment

PMID: 18215767 [PubMed] Deber CM et al: "Defining the defect in F508 del CFTR: a soluble problem?"

No. Sentence Comment

23 To address this question, Pissarra et al. (2008) report in this issue on the trafficking in mammalian cell lines of full-length CFTR proteins carrying wt, F508 del, or F508 del with the F494N/Q637R or F429S/F494N/ Q637R replacements. Login to comment
25 Strikingly, the solubilizing mutations, notably the triple mutant F429S/ F494N/Q637R, appeared to promote some N-glycan processing in F508 del CFTR, to produce Band C, along with bands of MW intermediate between those of Band B and Band C, suggesting that these replacements partially rescue the trafficking defect. Login to comment

PMID: 23378596 [PubMed] Hunt JF et al: "Cystic fibrosis transmembrane conductance regulator (ABCC7) structure."

No. Sentence Comment

164 (This mutation set is found in combination with the F409L, F429S, F433L, and H667R mutations in PDB IDs 1XMJ and 2BBO.) Login to comment
165 The other mutation sets that improved the yield of soluble hNBD1 involved substitution of surface-exposed residues in hNBD1 with more polar residues occurring at the same position in CFTR orthologs from other species (F429S/F494N/ Q637R found in PDB ID 2BBS, F494N/ Q637R found in PDB ID 2BBT, and F429S/ H667R found in PDB ID 1XMI). Login to comment
236 Note that the structures shown here contain seven point mutations included in hNBD1 constructs because of their beneficial influence on yield during purification-F409L, F429S, F433L, G550E, R553Q, R555K, and H667R. Login to comment

PMID: 23380248 [PubMed] Hanrahan JW et al: "Novel pharmacological strategies to treat cystic fibrosis."

No. Sentence Comment

146 Conversely, pharmacological chaperones that restore the interface between NBD1 and MSD2 should be additive with the three solubilizing (3S) mutant in NBD1 (F494N, Q637R, F429S) [11]. Login to comment

PMID: 23924900 [PubMed] Ren HY et al: "VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1."

No. Sentence Comment

93 These mutations are termed solubilizing (S) mutations and were introduced into NBD1 in different combinations (Figure 5A, S2 [F429S, Q637R] and S3 [F429S, F494N, and Q637R]). Login to comment
178 S2 (F429S, Q637R) and S3 (F429S, F494N, and Q637R) are mutations introduced into NBD1 to increase the thermodynamic stability of NBD1 and thereby increase CFTR and F508del-CFTR (B and C) folding efficiency (Pissarra et al., 2008; Teem et al., 1993). Login to comment

PMID: 24513531 [PubMed] Moran O et al: "On the structural organization of the intracellular domains of CFTR."

No. Sentence Comment

1241 However, as the native preparation of NBD1 and NBD2 tend to precipitate at relatively low concentration (>2.5 mg/ml; Galeno et al., 2011; Galfr&#e8; et al., 2012), to obtain protein concentrations compatible with the crystallization conditions, three to seven revertant mutations (F409L, F429S, F433L, G550E, R553Q, R555K, H667R, Roxo-Rosa et al., 2006; F429S, F494N, Q637R, Pissarra et al., 2008) have been introduced into the NBD1. Login to comment

PMID: 24737137 [PubMed] Phuan PW et al: "Synergy-based small-molecule screen using a human lung epithelial cell line yields DeltaF508-CFTR correctors that augment VX-809 maximal efficacy."

No. Sentence Comment

43 The cloning and characterization of 3HA-tagged variants of ƊF508-CFTR, R1070W- ƊF508-CFTR, and 3S-ƊF508-CFTR (containing the F494N, Q637R, and F429S NBD1 suppressor mutations) were described (Okiyoneda et al., 2013). Login to comment
101 Preferential correction of DF508-CFTR-3HA with the NBD1 stabilizing 3S mutations (F494N, Q637R, and F429S) compared with CFTR carrying the R1070W interface-stabilizing mutation has been taken as evidence that VX-809 preferentially stabilizes the interface between NBD1 and MSDs but not the NBD1 folding defect CFTR (Okiyoneda et al., 2013). Login to comment