6hep

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Crystal structure of human 14-3-3 beta in complex with CFTR R-domain peptide pS753-pS768

Structural highlights

6hep is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:ETE
NonStd Res:SEP
Gene:YWHAB (HUMAN)
Activity:Channel-conductance-controlling ATPase, with EC number 3.6.3.49
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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References

  1. ↑ Cutting GR, Kasch LM, Rosenstein BJ, Zielenski J, Tsui LC, Antonarakis SE, Kazazian HH Jr. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Nature. 1990 Jul 26;346(6282):366-9. PMID:1695717 doi:http://dx.doi.org/10.1038/346366a0
  2. ↑ Kerem BS, Zielenski J, Markiewicz D, Bozon D, Gazit E, Yahav J, Kennedy D, Riordan JR, Collins FS, Rommens JM, et al.. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. PMID:2236053
  3. ↑ White MB, Krueger LJ, Holsclaw DS Jr, Gerrard BC, Stewart C, Quittell L, Dolganov G, Baranov V, Ivaschenko T, Kapronov NI, et al.. Detection of three rare frameshift mutations in the cystic fibrosis gene in an African-American (CF444delA), an Italian (CF2522insC), and a Soviet (CF3821delT). Genomics. 1991 May;10(1):266-9. PMID:1710600
  4. ↑ Jones CT, McIntosh I, Keston M, Ferguson A, Brock DJ. Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. Hum Mol Genet. 1992 Apr;1(1):11-7. PMID:1284466
  5. ↑ Cheadle JP, Meredith AL, al-Jader LN. A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene. Hum Mol Genet. 1992 May;1(2):123-5. PMID:1284468
  6. ↑ Lissens W, Bonduelle M, Malfroot A, Dab I, Liebaers I. A serine to proline substitution (S1255P) in the second nucleotide binding fold of the cystic fibrosis gene. Hum Mol Genet. 1992 Sep;1(6):441-2. PMID:1284530
  7. ↑ Shackleton S, Beards F, Harris A. Detection of novel and rare mutations in exon 4 of the cystic fibrosis gene by SSCP. Hum Mol Genet. 1992 Sep;1(6):439-40. PMID:1284529
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  9. ↑ Mercier B, Lissens W, Novelli G, Kalaydjieva L, De Arce M, Kapranov N, Klain NC, Lenoir G, Chauveau P, Lenaerts C, et al.. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993 Apr;16(1):296-7. PMID:7683628
  10. ↑ Nunes V, Chillon M, Dork T, Tummler B, Casals T, Estivill X. A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype. Hum Mol Genet. 1993 Jan;2(1):79-80. PMID:7683954
  11. ↑ Chillon M, Casals T, Nunes V, Gimenez J, Perez Ruiz E, Estivill X. Identification of a new missense mutation (P205S) in the first transmembrane domain of the CFTR gene associated with a mild cystic fibrosis phenotype. Hum Mol Genet. 1993 Oct;2(10):1741-2. PMID:7505694
  12. ↑ Gasparini P, Marigo C, Bisceglia G, Nicolis E, Zelante L, Bombieri C, Borgo G, Pignatti PF, Cabrini G. Screening of 62 mutations in a cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes. Hum Mutat. 1993;2(5):389-94. PMID:7504969 doi:http://dx.doi.org/10.1002/humu.1380020511
  13. ↑ Ghanem N, Costes B, Girodon E, Martin J, Fanen P, Goossens M. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994 May 15;21(2):434-6. PMID:7522211 doi:http://dx.doi.org/S0888-7543(84)71290-0
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  15. ↑ Dork T, Mekus F, Schmidt K, Bosshammer J, Fislage R, Heuer T, Dziadek V, Neumann T, Kalin N, Wulbrand U, et al.. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994 Nov;94(5):533-42. PMID:7525450
  16. ↑ Greil I, Wagner K, Rosenkranz W. A new missense mutation G1249E in exon 20 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Hered. 1994 Jul-Aug;44(4):238-40. PMID:7520022
  17. ↑ Petreska L, Koceva S, Gordova-Muratovska A, Nestorov R, Efremov GD. Identification of two new mutations (711 +3A-->G and V1397E) in CF chromosomes of Albanian and Macedonian origin. Hum Mol Genet. 1994 Jun;3(6):999-1000. PMID:7524913
  18. ↑ Schaedel C, Kristoffersson AC, Kornfalt R, Holmberg L. A novel cystic fibrosis mutation, Y109C, in the first transmembrane domain of CFTR. Hum Mol Genet. 1994 Jun;3(6):1001-2. PMID:7524909
  19. ↑ Chillon M, Casals T, Gimenez J, Nunes V, Estivill X. Analysis of the CFTR gene in the Spanish population: SSCP-screening for 60 known mutations and identification of four new mutations (Q30X, A120T, 1812-1 G-->A, and 3667del4). Hum Mutat. 1994;3(3):223-30. PMID:7517264 doi:http://dx.doi.org/10.1002/humu.1380030308
  20. ↑ Bienvenu T, Petitpretz P, Beldjord C, Kaplan JC. A missense mutation (F87L) in exon 3 of the cystic fibrosis transmembrane conductance regulator gene. Hum Mutat. 1994;3(4):395-6. PMID:8081395 doi:http://dx.doi.org/10.1002/humu.1380030412
  21. ↑ Brancolini V, Cremonesi L, Belloni E, Pappalardo E, Bordoni R, Seia M, Russo S, Padoan R, Giunta A, Ferrari M. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995 Sep;96(3):312-8. PMID:7544319
  22. ↑ Desgeorges M, Rodier M, Piot M, Demaille J, Claustres M. Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype. Hum Genet. 1995 Dec;96(6):717-20. PMID:8522333
  23. ↑ Zielenski J, Markiewicz D, Chen HS, Schappert K, Seller A, Durie P, Corey M, Tsui LC. Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1995;5(1):43-7. PMID:7537150 doi:http://dx.doi.org/10.1002/humu.1380050106
  24. ↑ Verlingue C, Kapranov NI, Mercier B, Ginter EK, Petrova NV, Audrezet MP, Ferec C. Complete screening of mutations in the coding sequence of the CFTR gene in a sample of CF patients from Russia: identification of three novel alleles. Hum Mutat. 1995;5(3):205-9. PMID:7541273 doi:http://dx.doi.org/10.1002/humu.1380050304
  25. ↑ Romey MC, Desgeorges M, Ray P, Godard P, Demaille J, Claustres M. Novel missense mutation in the first transmembrane segment of the CFTR gene (Q98R) identified in a male adult. Hum Mutat. 1995;6(2):190-1. PMID:7581407 doi:http://dx.doi.org/10.1002/humu.1380060216
  26. ↑ Leoni GB, Pitzalis S, Podda R, Zanda M, Silvetti M, Caocci L, Cao A, Rosatelli MC. A specific cystic fibrosis mutation (T3381) associated with the phenotype of isolated hypotonic dehydration. J Pediatr. 1995 Aug;127(2):281-3. PMID:7543567
  27. ↑ Ferec C, Novelli G, Verlingue C, Quere I, Dallapiccola B, Audrezet MP, Mercier B. Identification of six novel CFTR mutations in a sample of Italian cystic fibrosis patients. Mol Cell Probes. 1995 Apr;9(2):135-7. PMID:7541510
  28. ↑ Messaoud T, Verlingue C, Denamur E, Pascaud O, Quere I, Fattoum S, Elion J, Ferec C. Distribution of CFTR mutations in cystic fibrosis patients of Tunisian origin: identification of two novel mutations. Eur J Hum Genet. 1996;4(1):20-4. PMID:8800923
  29. ↑ Nasr SZ, Strong TV, Mansoura MK, Dawson DC, Collins FS. Novel missense mutation (G314R) in a cystic fibrosis patient with hepatic failure. Hum Mutat. 1996;7(2):151-4. PMID:8829633 doi:<151::AID-HUMU10>3.0.CO;2-1 10.1002/(SICI)1098-1004(1996)7:2<151::AID-HUMU10>3.0.CO;2-1
  30. ↑ Petreska L, Plaseska D, Koceva S, Stavljenic-Rukavina A, Efremov GD. A novel mutation in exon 12 (Y569C) of the CFTR gene identified in a patient of Croatian origin. Hum Mutat. 1996;7(4):374-5. PMID:8723693 doi:10.1002/humu.1380070402
  31. ↑ Bienvenu T, Chertkoff L, Beldjord C, Segal E, Carniglia L, Barreiro C, Kaplan JC. Identification of three novel mutations in the cystic fibrosis transmembrane conductance regulator gene in Argentinian CF patients. Hum Mutat. 1996;7(4):376-7. PMID:8723695 doi:<376::AID-HUMU18>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)7:4<376::AID-HUMU18>3.0.CO;2-#
  32. ↑ Hughes DJ, Hill AJ, Macek M Jr, Redmond AO, Nevin NC, Graham CA. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996;8(4):340-7. PMID:8956039 doi:<340::AID-HUMU7>3.0.CO;2-B 10.1002/(SICI)1098-1004(1996)8:4<340::AID-HUMU7>3.0.CO;2-B
  33. ↑ 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
  34. ↑ 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
  35. ↑ 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
  36. ↑ Shrimpton AE, Borowitz D, Swender P. Cystic fibrosis mutation frequencies in upstate New York. Hum Mutat. 1997;10(6):436-42. PMID:9401006 doi:<436::AID-HUMU4>3.0.CO;2-B 10.1002/(SICI)1098-1004(1997)10:6<436::AID-HUMU4>3.0.CO;2-B
  37. ↑ Friedman KJ, Leigh MW, Czarnecki P, Feldman GL. Cystic fibrosis transmembrane-conductance regulator mutations among African Americans. Am J Hum Genet. 1998 Jan;62(1):195-6. PMID:9443874 doi:10.1086/301681
  38. ↑ Onay T, Topaloglu O, Zielenski J, Gokgoz N, Kayserili H, Camcioglu Y, Cokugras H, Akcakaya N, Apak M, Tsui LC, Kirdar B. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998 Feb;102(2):224-30. PMID:9521595
  39. ↑ Bombieri C, Benetazzo M, Saccomani A, Belpinati F, Gile LS, Luisetti M, Pignatti PF. Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease. Hum Genet. 1998 Dec;103(6):718-22. PMID:9921909
  40. ↑ Vankeerberghen A, Wei L, Jaspers M, Cassiman JJ, Nilius B, Cuppens H. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID:9736778
  41. ↑ Malone G, Haworth A, Schwarz MJ, Cuppens H, Super M. Detection of five novel mutations of the cystic fibrosis transmembrane regulator (CFTR) gene in Pakistani patients with cystic fibrosis: Y569D, Q98X, 296+12(T>C), 1161delC and 621+2(T>C). Hum Mutat. 1998;11(2):152-7. PMID:9482579 doi:<152::AID-HUMU8>3.0.CO;2-L 10.1002/(SICI)1098-1004(1998)11:2<152::AID-HUMU8>3.0.CO;2-L
  42. ↑ Leoni GB, Pitzalis S, Tonelli R, Cao A. Identification of a novel mutation (S13F) in the CFTR gene in a CF patient of Sardinian origin. Hum Mutat. 1998;11(4):337. PMID:9554753
  43. ↑ Feldmann D, Sardet A, Cougoureux E, Plouvier E, Fontaine JL, Tournier G, Aymard P. Identification of three novel mutations in the CFTR gene, R117P, deltaD192, and 3121-1G-->A in four French patients. Hum Mutat. 1998;Suppl 1:S78-80. PMID:9452048
  44. ↑ 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
  45. ↑ Shackleton S, Harris A. A 2-amino acid insertion mutation (1243insACAAAA) in exon 7 of the CFTR gene. Hum Mutat. 1998;Suppl 1:S156-7. PMID:9452073
  46. ↑ 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
  47. ↑ 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
  48. ↑ Jezequel P, Dorval I, Fergelot P, Chauvel B, Le Treut A, Le Gall JY, Le Lannou D, Blayau M. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 1995 Jun;41(6 Pt 1):833-5. PMID:7539342
  49. ↑ 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
  50. ↑ Bienvenu T, Bousquet S, Vidaud D, Hubert D, Francoual C, Beldjord C, Kaplan JC. A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in a French CBAVD patient. Mutations in brief no. 175. Online. Hum Mutat. 1998;12(3):213-4. PMID:10651488
  51. ↑ Liu Y, Ross JF, Bodine PV, Billiard J. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Mol Endocrinol. 2007 Dec;21(12):3050-61. Epub 2007 Aug 23. PMID:17717073 doi:http://dx.doi.org/10.1210/me.2007-0323
  52. ↑ 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
  53. ↑ 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
  54. ↑ 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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6hep, resolution 1.86Å

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