| 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
[1433B_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. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2.[51] [52] [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.[53]
Publication Abstract from PubMed
Protein-protein interactions (PPIs) are at the core of molecular control over cellular function. Multivalency in PPI formation, such as via proteins with multiple binding sites and different valencies, requires fundamental understanding to address correlated challenges in pathologies and drug development. Thermodynamic binding models are needed to provide frameworks for describing multivalent PPIs. We established a model based on ditopic host-guest systems featuring the effective molarity, a hallmark property of multivalency, as a prime parameter governing the intramolecular binding in divalent interactions. By way of illustration, we study the interaction of the bivalent 14-3-3 protein scaffold with both the nonavalent CFTR and the hexavalent LRRK2 proteins, determining the underlying thermodynamics and providing insights into the role of individual sites in the context of the multivalent platform. Fitting of binding data reveals enthalpy-entropy correlation in both systems. Simulations of speciations for the entire phosphorylated protein domains reveal that the CFTR protein preferably binds to 14-3-3 by combinations including the strongest binding site pS768, but that other binding sites take over when this site is eliminated, leading to only a minor decrease in total affinity for 14-3-3. For LRRK2, two binding sites dominate the complex formation with 14-3-3, but the distantly located pS1444 site also plays a role in complex formation. Thermodynamic modeling of these multivalent PPIs allowed analyzing and predicting the effects of individual sites regarding their modulation via, for example, (de)phosphorylation or small-molecule targeting. The results specifically bring forward the potential of PPI stabilization, as an entry for drug discovery for multivalent PPIs.
A Thermodynamic Model for Multivalency in 14-3-3 Protein-Protein Interactions.,Stevers LM, de Vink PJ, Ottmann C, Huskens J, Brunsveld L J Am Chem Soc. 2018 Oct 18. doi: 10.1021/jacs.8b09618. PMID:30296824[54]
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
- ↑ Casals T, Pacheco P, Barreto C, Gimenez J, Ramos MD, Pereira S, Pinheiro JA, Cobos N, Curvelo A, Vazquez C, Rocha H, Seculi JL, Perez E, Dapena J, Carrilho E, Duarte A, Palacio AM, Nunes V, Lavinha J, Estivill X. Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. Hum Mutat. 1997;10(5):387-92. PMID:9375855 doi:<387::AID-HUMU9>3.0.CO;2-C 10.1002/(SICI)1098-1004(1997)10:5<387::AID-HUMU9>3.0.CO;2-C
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- ↑ Casals T, Ramos MD, Gimenez J, Nadal M, Nunes V, Estivill X. Paternal origin of a de novo novel CFTR mutation (L1065R) causing cystic fibrosis. Hum Mutat. 1998;Suppl 1:S99-102. PMID:9452054
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- ↑ Picci L, Cameran M, Olante P, Zacchello F, Scarpa M. Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Mutations in brief no. 221. Online. Hum Mutat. 1999;13(2):173. PMID:10094564 doi:<173::AID-HUMU19>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)13:2<173::AID-HUMU19>3.0.CO;2-E
- ↑ 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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- ↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
- ↑ 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, de Vink PJ, Ottmann C, Huskens J, Brunsveld L. A Thermodynamic Model for Multivalency in 14-3-3 Protein-Protein Interactions. J Am Chem Soc. 2018 Oct 18. doi: 10.1021/jacs.8b09618. PMID:30296824 doi:http://dx.doi.org/10.1021/jacs.8b09618
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