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PDBsum entry 1xf9
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Transport protein
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PDB id
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1xf9
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References listed in PDB file
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Key reference
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Title
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Side chain and backbone contributions of phe508 to cftr folding.
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Authors
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P.H.Thibodeau,
C.A.Brautigam,
M.Machius,
P.J.Thomas.
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Ref.
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Nat Struct Mol Biol, 2005,
12,
10-16.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an
integral membrane protein, cause cystic fibrosis (CF). The most common
CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the
role Phe508 plays in the folding of CFTR, missense mutations at this position
were generated. Only one missense mutation had a pronounced effect on the
stability and folding of the isolated domain in vitro. In contrast, many
substitutions, including those of charged and bulky residues, disrupted folding
of full-length CFTR in cells. Structures of two mutant nucleotide-binding
domains (NBDs) reveal only local alterations of the surface near position 508.
These results suggest that the peptide backbone plays a role in the proper
folding of the domain, whereas the side chain plays a role in defining a surface
of NBD1 that potentially interacts with other domains during the maturation of
intact CFTR.
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Figure 3.
Figure 3. Maturation of full-length CFTR mutants.
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Figure 4.
Figure 4. ABC transporter structure and CFTR biogenesis. (a)
Crystal structure of the BtuCD ABC-transport systems21. The
Escherichia coli vitamin D transporter system BtuCD structures
(PDB entry 1L7V) are shown with the Phe508-analogous residue
Leu96 shown in red spheres at the NBD-TMD interfaces. The BtuC
transmembrane proteins are blue and the BtuD NBDs are yellow.
Two views of the BtuCD complex are shown rotated about the
vertical axis by  90°.
(b) Hierarchical folding of CFTR. Step 1, TMD1 is translated and
inserted into the membrane. Pale blue indicates the reduced
stability of TMD1 in the absence of NBD1. Step 2, NBD1 is
translated and folds into a native or near-native state. The
blurred image of the mNBD1 structure indicates the attainment of
a native or near-native state, which is most likely stabilized
by interactions with additional CFTR domains. Step 3, NBD1 docks
against TMD1. This event probably leads to the stabilization of
both NBD1 and TMD1, as shown by the change in blue color in the
TMD and the sharpening of the NBD1 structure. This is followed
by the translation, folding and assembly of the domains
C-terminal to NBD1. Mutations that putatively affect each step
are in parentheses. The NBDs are represented by the mNBD1
structure and are oriented relative to the NBD dimer and TMD
-NBD complex seen in BtuCD with the assumption that CFTR is
monomeric with a functional NBD1 -NBD2 heterodimer.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2005,
12,
10-16)
copyright 2005.
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