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Cystic FibrosisTransmembrane Conductance Regulator and Filamin A

Cystic FibrosisTransmembrane Conductance Regulator and Filamin A. Background for “Biochemical Basis of the Interaction between Cystic Fibrosis Transmembrane Conductance Regulator and Immunoglobulin-like Repeats of Filamin” Smith et al. JBC 285 (2010): 17166-17176. Web.

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Cystic FibrosisTransmembrane Conductance Regulator and Filamin A

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  1. Cystic FibrosisTransmembrane Conductance Regulator and Filamin A Background for “Biochemical Basis of the Interaction between Cystic Fibrosis Transmembrane Conductance Regulator and Immunoglobulin-like Repeats of Filamin” Smith et al. JBC 285 (2010): 17166-17176. Web. Presented by Amanda Maez March 9, 2011

  2. Cystic Fibrosis • Most common, lethal genetic disorder in Caucasians characterized by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) of epithelial cells • Characterized by high sweat chloride concentration and dehydrated viscous secretions • Most common mutation is the F508 • ~30,000 individuals in North America are affected (70% carry one copy of F508)

  3. Presentation Overview • CFTR • Location • ABC transporter- general structure • Structure and Function • Mutations • Filamin A • Actin binding protein (ABP) • Structure • Basis for Research of Smith et al. • Mutants are rapidly degraded in ER • S13F mutation disrupts CFTR-filamin interaction

  4. CFTR is an ABC Transporter • ATP binding cassette transporter • 2 Membrane spanning domains (MSD1 and MSD2) • 2 Nucleotide binding domains (NBD1 and NBD2) • Motor • Humans have at least 48 (3-5% of bacterial genome) K P Locher et al. Science 2002;296:1091-1098

  5. CFTR Structure • 2 MSDs • 6 membrane-spanning -helices in each • 2 NBDs • Each possess an ATP binding pocket • ABP1 formed by Walker A and B motifs of NBD1, ABP2 by Walker A and B motifs of NBD2 • Unique regulatory (R) region • Located between the NH2 terminal NBD and the second MSD

  6. Structure of CFTR Chen, Tsung-Yu, and Tzyh-chang Hwang. "CLC-O and CFTR: Chloride Channels Evolved From Transporters." Physiological Reviews 88 (2008): 351-87. Web

  7. CFTR Function • Conducts Cl¯ across membrane when both NBDs have bound ATP and R domain is phosphorylated by protein kinase A • Closes when ATP is hydrolyzed on one of the NBDs and R domain is no longer phosphorylated. Lehninger. Principles of Biochemistry. 5th Edition. W.H. Freeman and Company, 2008. 401. Print.

  8. Mutations in CFTR • Most common is the F508, which is located in NBD1 • Cause misfolding of the protein which lead to a defective channel due to inability to hydrolyze ATP • Decrease in Cl¯ export is accompanied with a decrease in export of water and leads to thick, sticky mucus which is a haven for bacteria that are the ultimate cause of mortality • These mutated CFTRs are rapidly transported to and degraded in the ER • Those that are not degraded are usually subject to inefficient trafficking to the apical plasma membrane

  9. Filamin A Structure • High molecular weight • Long rod-like domain of 24 repeated anti-parallel -sheets (resembling immunoglobulin domain) • Two flexible loops (30 aa) that form hinge structures

  10. Fln A Structure • Crystal Structure of C2 Fragment of Steptococcal protein G in complex with FC domain of Human IgG Smith et al. JBC 285 (2010), Supplemental Figures. Sauer-Eriksson et al. Structure 3 (1995). Web. • Details of FlnA-Ig21:CFTR4-22 crystal structure

  11. Filamin A Function • Actin Binding Protein (ABP) • F-actin crosslinker--scaffolding protein • Anchors a variety of transmembrane proteins to the actin cytoskeleton

  12. Fln A Function Nakamura et al. JCB179 (2007): 1011-1025. Web.

  13. Basis for Research of Smith et al. • Mutated CFTRs are rapidly transported to and degraded in the ER • Those that are not degraded maintain partial function, but are usually subject to inefficient trafficking to the apical plasma membrane • Filamin A anchors CFTR to the actin skeleton • Understand the interaction between Filamin A and CFTR using a mutation (S13F) that disrupts this binding

  14. Sources • Chen, Tsung-Yu, and Tzyh-chang Hwang. "CLC-O and CFTR: Chloride Channels Evolved From Transporters." Physiological Reviews 88 (2008): 351-87. Web. • Feng, Yuanyi, and Christopher Walsh. "The Many Faces of Filamin: A Versatile Molecular Scaffold for Cell Motility and Cignaling." Nature Cell Biology 6.11 (2004): 1034-038. Web. • Nakamura et al. “Structural Basis of Filamin A functions.”JCB 179 (2007): 1011-1025. Web. • Locher, Kaspar. "The E. Coli BtuCD Structure: a Framework for ABC Transporter Architecture and Mechanism." Ribbon diagram of the BtuCD protein structure. Science 296 (2002): 1091-098. Web Image. • Sauer-Eriksson, A.E. "Crystal Structure of the C2 Fragment of Streptococcal Protein G in Complex with the Fc Domain of Human IgG." Structure 3 (1995): 265-78. RCSB Protein Data Bank. Web. 8 Mar. 2011. • Smith et al. “Biochemical Basis of the Interaction between Cystic Fibrosis Transmembrane Conductance Regulator and Immunoglobulin-like Repeats of Filamin.” Journal of Biological Chemistry 285 (2010): 17166-17176. Web. • Uribe, Ricardo, and David Jay. "A Review of Actin Binding Proteins: New Perspectives." Molecular Biology Reports 36 (2007): 121-25. Print.

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