Literature summary for 5.6.1.6 extracted from

Cui, G.; Freeman, C.S.; Knotts, T.; Prince, C.Z.; Kuang, C.; McCarty, N.A.
Two salt bridges differentially contribute to the maintenance of cystic fibrosis transmembrane conductance regulator (CFTR) channel function (2013), J. Biol. Chem., 288, 20758-20767.

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Protein Variants

Protein Variants	Comment	Organism
D924R	site-directed mutagenesis, the mutant shows brief transitions to all conductance levels, it can reach the open state but not stably	Homo sapiens
D993R	site-directed mutagenesis, the mutant opens to all 3 levels, but none are stable. The mutant can reach the open state but not stably	Homo sapiens
R347A	site-directed mutagenesis, the mutant emphasizes s1 state, brief transitions to s2 state and the open state, it can reach the open state but not stably	Homo sapiens
R347A/R352A	site-directed mutagenesis, the mutant opens to all 3 levels, s1 state is much more stable than in the wild-type, s2 state is unstable, the open state is unstable. The mutant can reach the open state but not stably	Homo sapiens
R347D	site-directed mutagenesis, the mutant emphasizes s1 state, no transitions to s2 state and the open state, the mutant cannot reach the open state	Homo sapiens
R347D/D924R	site-directed mutagenesis, the mutant emphasizes s2 state, rare and brief transitions to the open state, it can reach the open state but not stably	Homo sapiens
R347D/D924R/D993R	site-directed mutagenesis, the mutant opens to all 3 levels, s1 state is much more stable than in the wild-type, s2 state is relatively stabilized, the open state is unstable. The mutant can reach the open state but not stably	Homo sapiens
R347D/D924R/R352E/D993R	site-directed mutagenesis, the mutant primarily flickers between s2 state and the open state, s1 state is much more stable than in the wild-type, the mutant shows slightly reduced single channel conductance, it can reach the open state but not stably	Homo sapiens
R347D/D993R	site-directed mutagenesis, the mutant shows very stable s2 state, but rare and brief transitions to both s1 state and the open state. It can reach the open state but not stably	Homo sapiens
R347K	site-directed mutagenesis, the mutant is wild-type-like	Homo sapiens
R352E	site-directed mutagenesis, the mutant opens to all 3 levels, s1 state is much more stable than in wild-type, s2 state is unstable, the open state is unstable. The mutant can reach the open state but not stably	Homo sapiens
R352E/D924R	site-directed mutagenesis, the mutant opens to all 3 levels, but none are stable. The mutant can reach the open state but not stably	Homo sapiens
R352E/D993R	site-directed mutagenesis, the mutant is wild type-like, with increased transitions to s1 and s2 states, it shows slightly reduced single-channel conductance, the impact on the open state is wild type-like	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
additional information	Homo sapiens	two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P13569	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge	Homo sapiens	?	-	?

Synonyms

Synonyms	Comment	Organism
CFTR	-	Homo sapiens
cystic fibrosis transmembrane conductance regulator	-	Homo sapiens

General Information

General Information	Comment	Organism
additional information	CFTR homology model indicating two salt bridges, using the homology model from the Riordan group. Residues Arg347, Asp924, and Asp993 form a triangular salt bridge early in channel openings, whereas Arg352 and Asp993 interact late in channel opening	Homo sapiens
physiological function	the enzyme acts as a chloride ion channel, CFTR channel pore opening is accomplished by R domain phosphorylation and the binding of ATP at the nucleotide-binding domains, where the two membrane-spanning domains are driven to change conformation to allow anions to flow, mode of action, overview	Homo sapiens

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Release 2023.1 (January 2023)