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Association of the cystic fibrosis transmembrane regulator with CAL: structural features and molecular dynamics.

Piserchio A, Fellows A, Madden DR, Mierke DF
Biochemistry 44 16158-66 (2005)
Cited: 19 times
EuropePMC logo PMID: 16331976

Abstract

The association of the cystic fibrosis transmembrane regulator (CFTR) with two PDZ-containing molecular scaffolds (CAL and EBP50) plays an important role in CFTR trafficking and membrane maintenance. The CFTR-molecular scaffold interaction is mediated by the association of the C-terminus of the transmembrane regulator with the PDZ domains. Here, we characterize the structure and dynamics of the PDZ of CAL and the complex formed with CFTR employing high-resolution NMR. On the basis of NMR relaxation data, the alpha2 helix as well as the beta2-beta3 loop of CAL PDZ domain undergoes rapid dynamics. Molecular dynamics simulations suggest a concerted motion between the alpha2 helix and the beta1-beta2 and beta2-beta3 loops, elements which define the binding pocket, suggesting that dynamics may play a role in PDZ-ligand specificity. The C-terminus of CFTR binds to CAL with the final four residues (-D(-)(3)-T-R-L(0)) within the canonical PDZ-binding motif, between the beta2 strand and the alpha2 helix. The R(-)(1) and D(-)(3) side chains make a number of contacts with the PDZ domain; many of these interactions differ from those in the CFTR-EBP50 complex, suggesting sites that can be targeted in the development of PDZ-selective inhibitors that may help modulate CFTR function.

Articles - 2lob mentioned but not cited (6)

  1. Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity. Roberts KE, Cushing PR, Boisguerin P, Madden DR, Donald BR. PLoS Comput Biol 8 e1002477 (2012)
  2. Stereochemical determinants of C-terminal specificity in PDZ peptide-binding domains: a novel contribution of the carboxylate-binding loop. Amacher JF, Cushing PR, Bahl CD, Beck T, Madden DR. J Biol Chem 288 5114-5126 (2013)
  3. Cysteine modifiers suggest an allosteric inhibitory site on the CAL PDZ domain. Zhao Y, Cushing PR, Smithson DC, Pellegrini M, Pletnev AA, Al-Ayyoubi S, Grassetti AV, Gerber SA, Guy RK, Madden DR. Biosci Rep 38 BSR20180231 (2018)
  4. Computational Analysis of Energy Landscapes Reveals Dynamic Features That Contribute to Binding of Inhibitors to CFTR-Associated Ligand. Holt GT, Jou JD, Gill NP, Lowegard AU, Martin JW, Madden DR, Donald BR. J Phys Chem B 123 10441-10455 (2019)
  5. Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures. Dudola D, Hinsenkamp A, Gáspári Z. Int J Mol Sci 21 E8348 (2020)
  6. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (2)

  1. Emerging Themes in PDZ Domain Signaling: Structure, Function, and Inhibition. Liu X, Fuentes EJ. Int Rev Cell Mol Biol 343 129-218 (2019)
  2. Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives. Brusa I, Sondo E, Falchi F, Pedemonte N, Roberti M, Cavalli A. J Med Chem 65 5212-5243 (2022)

Articles citing this publication (11)

  1. The relative binding affinities of PDZ partners for CFTR: a biochemical basis for efficient endocytic recycling. Cushing PR, Fellows A, Villone D, Boisguérin P, Madden DR. Biochemistry 47 10084-10098 (2008)
  2. A stabilizing influence: CAL PDZ inhibition extends the half-life of ΔF508-CFTR. Cushing PR, Vouilleme L, Pellegrini M, Boisguerin P, Madden DR. Angew Chem Int Ed Engl 49 9907-9911 (2010)
  3. Targeting CAL as a negative regulator of DeltaF508-CFTR cell-surface expression: an RNA interference and structure-based mutagenetic approach. Wolde M, Fellows A, Cheng J, Kivenson A, Coutermarsh B, Talebian L, Karlson K, Piserchio A, Mierke DF, Stanton BA, Guggino WB, Madden DR. J Biol Chem 282 8099-8109 (2007)
  4. DeltaF508 mutation increases conformational flexibility of CFTR protein. Wieczorek G, Zielenkiewicz P. J Cyst Fibros 7 295-300 (2008)
  5. Solution structure of GOPC PDZ domain and its interaction with the C-terminal motif of neuroligin. Li X, Zhang J, Cao Z, Wu J, Shi Y. Protein Sci 15 2149-2158 (2006)
  6. Hybrid organic-inorganic inhibitors of a PDZ interaction that regulates the endocytic fate of CFTR. Kundu R, Cushing PR, Popp BV, Zhao Y, Madden DR, Ball ZT. Angew Chem Int Ed Engl 51 7217-7220 (2012)
  7. Novel mutations and polymorphisms in the CFTR gene associated with three subtypes of congenital absence of vas deferens. Yang X, Sun Q, Yuan P, Liang H, Wu X, Lai L, Zhang Y. Fertil Steril 104 1268-75.e1-2 (2015)
  8. Serum- and glucocorticoid-induced protein kinase 1 (SGK1) increases the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells by phosphorylating Shank2E protein. Koeppen K, Coutermarsh BA, Madden DR, Stanton BA. J Biol Chem 289 17142-17150 (2014)
  9. Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains. Boucherle B, Vogrig A, Deokar H, Bouzidi N, Ripoche I, Thomas I, Marin P, Ducki S. Bioorg Med Chem 19 4346-4354 (2011)
  10. Crystallization and preliminary diffraction analysis of the CAL PDZ domain in complex with a selective peptide inhibitor. Amacher JF, Cushing PR, Weiner JA, Madden DR. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 600-603 (2011)
  11. Exploring binding positions and backbone conformations of peptide ligands of proteins with a backbone-centred statistical energy function. Zhang L, Liu H. J Comput Aided Mol Des 37 463-478 (2023)


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