Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: In silico and functional characterisation of an ultra-rare CFTR mutation identifies novel lasso motif interactions regulating channel gating Characterisation of I37R - a novel mutation in the lasso motif of ABC-transporter CFTR, a chloride channel - was conducted by theratyping using CFTR potentiators which increase channel gating activity and correctors which repair protein trafficking defects. I37R-CFTR function was characterised using intestinal current measurements (ICM) in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids and short circuit current measurements (Isc) in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype. We demonstrated that the I37R-CFTR mutation results in a residual function defect amenable to treatment with potentiators and type III, but not to type I, correctors. Molecular dynamics of I37R-CFTR using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavourable strengthening of the interactions between the lasso motif, the regulatory (R) domain and the transmembrane domain two (TMD2). In conclusion, structural and functional characterisation of the I37R-CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to access CFTR modulator treatments for individuals with CF caused by ultra-rare CFTR mutations.
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The categories of this paper are: communication
1
The categories of this paper are: bioinformatics
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The categories of this paper are: pathology
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The categories of this paper are: cognition
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The categories of this paper are: microbiology
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The categories of this paper are: epidemiology
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The categories of this paper are: genomics
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The categories of this paper are: synthetic
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The categories of this paper are: cell
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The categories of this paper are: paleontology
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The categories of this paper are: toxicology
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The categories of this paper are: ecology
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The categories of this paper are: education
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The categories of this paper are: zoology
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The categories of this paper are: pharmacology
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The categories of this paper are: immunology