| Structural highlights
Disease
[CFTR_HUMAN] Defects in CFTR are the cause of cystic fibrosis (CF) [MIM:219700]; also known as mucoviscidosis. CF is the most common genetic disease in the Caucasian population, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. CF is a common generalized disorder of exocrine gland function which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] Defects in CFTR are the cause of congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180]. CBAVD is an important cause of sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens.[47] [48] [49] [50] [:]
Function
[1433Z_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[51] [52] [53] [54] [55] [CFTR_HUMAN] Involved in the transport of chloride ions. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the SLC4A7 transporter. Can inhibit the chloride channel activity of ANO1.[56]
Publication Abstract from PubMed
Cystic fibrosis is a fatal genetic disease, most frequently caused by the retention of the CFTR (cystic fibrosis transmembrane conductance regulator) mutant protein in the endoplasmic reticulum (ER). The binding of the 14-3-3 protein to the CFTR regulatory (R) domain has been found to enhance CFTR trafficking to the plasma membrane. To define the mechanism of action of this protein-protein interaction, we have examined the interaction in vitro. The disordered multiphosphorylated R domain contains nine different 14-3-3 binding motifs. Furthermore, the 14-3-3 protein forms a dimer containing two amphipathic grooves that can potentially bind these phosphorylated motifs. This results in a number of possible binding mechanisms between these two proteins. Using multiple biochemical assays and crystal structures, we show that the interaction between them is governed by two binding sites: The key binding site of CFTR (pS768) occupies one groove of the 14-3-3 dimer, and a weaker, secondary binding site occupies the other binding groove. We show that fusicoccin-A, a natural-product tool compound used in studies of 14-3-3 biology, can stabilize the interaction between 14-3-3 and CFTR by selectively interacting with a secondary binding motif of CFTR (pS753). The stabilization of this interaction stimulates the trafficking of mutant CFTR to the plasma membrane. This definition of the druggability of the 14-3-3-CFTR interface might offer an approach for cystic fibrosis therapeutics.
Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR.,Stevers LM, Lam CV, Leysen SF, Meijer FA, van Scheppingen DS, de Vries RM, Carlile GW, Milroy LG, Thomas DY, Brunsveld L, Ottmann C Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1152-61. doi:, 10.1073/pnas.1516631113. Epub 2016 Feb 17. PMID:26888287[57]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Clavel C, Pennaforte F, Pigeon F, Verlingue C, Birembaut P, Ferec C. Identification of four novel mutations in the cystic fibrosis transmembrane conductance regulator gene: E664X, 2113delA, 306delTAGA, and delta M1140. Hum Mutat. 1997;9(4):368-9. PMID:9101301 doi:<368::AID-HUMU13>3.0.CO;2-0 10.1002/(SICI)1098-1004(1997)9:4<368::AID-HUMU13>3.0.CO;2-0
- ↑ Gouya L, Pascaud O, Munck A, Elion J, Denamur E. Novel mutation (A141D) in exon 4 of the CFTR gene identified in an Algerian patient. Hum Mutat. 1997;10(1):86-7. PMID:9222768 doi:<86::AID-HUMU15>3.0.CO;2-W 10.1002/(SICI)1098-1004(1997)10:1<86::AID-HUMU15>3.0.CO;2-W
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- ↑ Mercier B, Verlingue C, Lissens W, Silber SJ, Novelli G, Bonduelle M, Audrezet MP, Ferec C. Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients. Am J Hum Genet. 1995 Jan;56(1):272-7. PMID:7529962
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- ↑ Zielenski J, Patrizio P, Markiewicz D, Asch RH, Tsui LC. Identification of two mutations (S50Y and 4173delC) in the CFTR gene from patients with congenital bilateral absence of vas deferens (CBAVD). Hum Mutat. 1997;9(2):183-4. PMID:9067761 doi:<183::AID-HUMU13>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1997)9:2<183::AID-HUMU13>3.0.CO;2-Z
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- ↑ Ousingsawat J, Kongsuphol P, Schreiber R, Kunzelmann K. CFTR and TMEM16A are separate but functionally related Cl- channels. Cell Physiol Biochem. 2011;28(4):715-24. doi: 10.1159/000335765. Epub 2011 Dec, 14. PMID:22178883 doi:10.1159/000335765
- ↑ Stevers LM, Lam CV, Leysen SF, Meijer FA, van Scheppingen DS, de Vries RM, Carlile GW, Milroy LG, Thomas DY, Brunsveld L, Ottmann C. Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR. Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1152-61. doi:, 10.1073/pnas.1516631113. Epub 2016 Feb 17. PMID:26888287 doi:http://dx.doi.org/10.1073/pnas.1516631113
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