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  • 1
    Online Resource
    Online Resource
    Asymmetric Structure of the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore Suggested by Mutagenesis of the Twelfth Transmembrane Region
    American Chemical Society (ACS) ; 2001
    In:  Biochemistry Vol. 40, No. 22 ( 2001-06-01), p. 6620-6627
    Details
    In: Biochemistry, American Chemical Society (ACS), Vol. 40, No. 22 ( 2001-06-01), p. 6620-6627
    Type of Medium: Online Resource
    ISSN: 0006-2960 , 1520-4995
    URL: Article
    DOI: 10.1021/bi002819v
    RVK:
    WA 15000
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2001
    detail.hit.zdb_id: 1108-3
    detail.hit.zdb_id: 1472258-6
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Phosphorylation of CFTR by PKA promotes binding of the regulatory domain
    Springer Science and Business Media LLC ; 2005
    In:  The EMBO Journal Vol. 24, No. 15 ( 2005-8-3), p. 2730-2740
    Details
    In: The EMBO Journal, Springer Science and Business Media LLC, Vol. 24, No. 15 ( 2005-8-3), p. 2730-2740
    Type of Medium: Online Resource
    ISSN: 0261-4189 , 1460-2075
    URL: Article
    DOI: 10.1038/sj.emboj.7600747
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2005
    detail.hit.zdb_id: 1467419-1
    detail.hit.zdb_id: 586044-1
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Insights into PCSK9-LDLR Regulation and Trafficking via the Differential Functions of MHC-I Proteins HFE and HLA-C
    MDPI AG ; 2024
    In:  Cells Vol. 13, No. 10 ( 2024-05-17), p. 857-
    Details
    In: Cells, MDPI AG, Vol. 13, No. 10 ( 2024-05-17), p. 857-
    Abstract: PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9’s C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified “protein X”. The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be “protein X” candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9’s function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of PCSK9’s functions through interactions of HFE and HLA-C.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells13100857
    Language: English
    Publisher: MDPI AG
    Publication Date: 2024
    detail.hit.zdb_id: 2661518-6
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  • 4
    Online Resource
    Online Resource
    Stimulatory and inhibitory protein kinase C consensus sequences regulate the cystic fibrosis transmembrane conductance regulator
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 1 ( 2004-01-06), p. 390-395
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 1 ( 2004-01-06), p. 390-395
    Abstract: Protein kinase C (PKC) phosphorylation stimulates the cystic fibrosis transmembrane conductance regulator (CFTR) channel and enhances its activation by protein kinase A (PKA) through mechanisms that remain poorly understood. We have examined the effects of mutating consensus sequences for PKC phosphorylation and report here evidence for both stimulatory and inhibitory sites. Sequences were mutated in subsets and the mutants characterized by patch clamping. Activation of a 4CA mutant (S707A/S790A/T791A/S809A) by PKA was similar to that of wild-type CFTR and was enhanced by PKC, whereas responses of 3CA (T582A/T604A/S641A) and 2CA (T682A/S686A) channels to PKA were both drastically reduced ( 〉 90%). When each mutation in the 3CA and 2CA constructs was studied individually in a wild-type background, T582, T604, and S686 were found to be essential for PKA activation. Responses were restored when these three residues were reintroduced simultaneously into a 9CA mutant lacking all nine PKC consensus sequences (R6CA revertant); however, PKC phosphorylation was not required for this rescue. Nevertheless, two of the sites (T604 and S686) were phosphorylated in vitro , and PKC alone partially activated wild-type CFTR, the 4CA mutant, and the point mutants T582A and T604A, but not S686A channels, indicating that PKC does act at S686. The region encompassing S641 and T682 is inhibitory, because S641A enhanced activation by PKA, and T682A channels had 4-fold larger responses to PKC compared to wild-type channels. These results identify functionally important PKC consensus sequences on CFTR and will facilitate studies of its convergent regulation by PKC and PKA.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0303411101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Erratum for Essalmani et al., “Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity”
    American Society for Microbiology ; 2022
    In:  Journal of Virology Vol. 96, No. 13 ( 2022-07-13)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 96, No. 13 ( 2022-07-13)
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00745-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 1495529-5
    detail.hit.zdb_id: 80174-4
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  • 6
    Online Resource
    Online Resource
    PKC phosphorylation modulates PKA-dependent binding of the R domain to other domains of CFTR
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Cell Physiology Vol. 295, No. 5 ( 2008-11), p. C1366-C1375
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 295, No. 5 ( 2008-11), p. C1366-C1375
    Abstract: Activity of the CFTR channel is regulated by phosphorylation of its regulatory domain (RD). In a previous study, we developed a bicistronic construct called ΔR-Split CFTR, which encodes the front and back halves of CFTR as separate polypeptides without the RD. These fragments assemble to form a constitutively active CFTR channel. Coexpression of the third fragment corresponding to the missing RD restores regulation by PKA, and this is associated with dramatically enhanced binding of the phosphorylated RD. In the present study, we examined the effect of PKC phosphorylation on this PKA-induced interaction. We report here that PKC alone enhanced association of the RD with ΔR-Split CFTR and that binding was further enhanced when the RD was phosphorylated by both kinases. Mutation of all seven PKC consensus sequences on the RD (7CA-RD) did not affect its association under basal (unphosphorylated) conditions but abolished phosphorylation-induced binding by both kinases. Iodide efflux responses provided further support for the essential role of RD binding in channel regulation. The basal activity of ΔR-Split/7CA-RD channels was similar to that of ΔR-Split/wild type (WT)-RD channels, whereas cAMP-stimulated iodide efflux was greatly diminished by removal of the PKC sites, indicating that 7CA-RD binding maintains channels in an inactive state that is unresponsive to PKA. These results suggest a novel mechanism for CFTR regulation in which PKC modulates PKA-induced domain-domain interactions.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00034.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477334-X
    detail.hit.zdb_id: 392098-7
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Regulation of the CFTR channel by phosphorylation
    Springer Science and Business Media LLC ; 2001
    In:  Pfl�gers Archiv European Journal of Physiology Vol. 443, No. 0 ( 2001-11-1), p. S92-S96
    Details
    In: Pfl�gers Archiv European Journal of Physiology, Springer Science and Business Media LLC, Vol. 443, No. 0 ( 2001-11-1), p. S92-S96
    Type of Medium: Online Resource
    ISSN: 0031-6768 , 1432-2013
    URL: Article
    DOI: 10.1007/s004240100652
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2001
    detail.hit.zdb_id: 6380-0
    detail.hit.zdb_id: 1463014-X
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Basolateral chloride loading by the anion exchanger type 2: role in fluid secretion by the human airway epithelial cell line Calu‐3
    Wiley ; 2012
    In:  The Journal of Physiology Vol. 590, No. 21 ( 2012-11), p. 5299-5316
    Details
    In: The Journal of Physiology, Wiley, Vol. 590, No. 21 ( 2012-11), p. 5299-5316
    Abstract: The companion paper provided evidence for basolateral anion exchange during cAMP stimulation of chloride and fluid secretion by Calu‐3 monolayers; however, the molecular basis of this transport was not identified. To test the role of AE2, an anion exchanger expressed at the basolateral membrane of Calu‐3 and many other epithelial cells, we used lentivirus‐mediated RNA interference to generate a stable Calu‐3 AE2 knock‐down cell line and characterized its fluid and anion transport properties. AE2 knock‐down suppressed fluid secretion and increased the fraction of cAMP‐stimulated anion secretion that was sensitive to bumetanide inhibition. Basolateral Cl − /HCO 3 − exchange was nearly abolished in AE2 knock‐down cells. We conclude that AE2 is active during forskolin‐stimulated fluid secretion and mediates chloride uptake and bicarbonate recycling at the basolateral membrane. Abstract  Anion exchanger type 2 (AE2 or SLC4A2) is an electroneutral Cl − /HCO 3 − exchanger expressed at the basolateral membrane of many epithelia. It is thought to participate in fluid secretion by airway epithelia. However, the role of AE2 in fluid secretion remains uncertain, due to the lack of specific pharmacological inhibitors, and because it is electrically silent and therefore does not contribute directly to short‐circuit current ( I sc ). We have studied the role of AE2 in Cl − and fluid secretion by the airway epithelial cell line Calu‐3. After confirming expression of its mRNA and protein, a knock‐down cell line called AE2‐KD was generated by lentivirus‐mediated RNA interference in which AE2 mRNA and protein levels were reduced ≥90%. Suppressing AE2 increased the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) by ∼70% without affecting the levels of NKCC1 (Na + –K + –2Cl − cotransporter) or NBCe1 (Na + –nHCO 3 − cotransporter). cAMP agonists stimulated fluid secretion by parental Calu‐3 and scrambled shRNA cells 〉 6.5‐fold. In AE2‐KD cells this response was reduced by ∼70%, and the secreted fluid exhibited elevated pH and [HCO 3 − ] as compared with the control lines. Unstimulated equivalent short‐circuit current ( I eq ) was elevated in AE2‐KD cells, but the incremental response to forskolin was unaffected. The modest bumetanide‐induced reductions in both I eq and fluid secretion were more pronounced in AE2‐KD cells. Basolateral Cl − /HCO 3 − exchange measured by basolateral pH‐stat in cells with permeabilized apical membranes was abolished in AE2‐KD monolayers, and the intracellular alkalinization resulting from basolateral Cl − removal was reduced by ∼80% in AE2‐KD cells. These results identify AE2 as a major pathway for basolateral Cl − loading during cAMP‐stimulated secretion of Cl − and fluid by Calu‐3 cells, and help explain the large bumetanide‐insensitive component of fluid secretion reported previously in airway submucosal glands and some other epithelia.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    URL: Article
    DOI: 10.1113/tjp.2012.590.issue-21
    DOI: 10.1113/jphysiol.2012.236919
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 1475290-6
    detail.hit.zdb_id: 3115-X
    SSG: 12
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  • 9
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    Online Resource
    Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor)
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 39, No. 10 ( 2019-10), p. 1996-2013
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 10 ( 2019-10), p. 1996-2013
    Abstract: PCSK9 (proprotein convertase subtilisin-kexin 9) enhances the degradation of the LDLR (low-density lipoprotein receptor) in endosomes/lysosomes. This study aimed to determine the sites of PCSK9 phosphorylation at Ser-residues and the consequences of such posttranslational modification on the secretion and activity of PCSK9 on the LDLR. Approach and Results: Fam20C (family with sequence similarity 20, member C) phosphorylates serines in secretory proteins containing the motif S-X-E/phospho-Ser, including the cholesterol-regulating PCSK9. In situ hybridization of Fam20C mRNA during development and in adult mice revealed a wide tissue distribution, including liver, but not small intestine. Here, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668, and 688. In hepatocytes, phosphorylation enhances PCSK9 secretion and maximizes its induced degradation of the LDLR via the extracellular and intracellular pathways. Replacing any of the 4 Ser by the phosphomimetic Glu or Asp enhanced PCSK9 activity only when the other sites are phosphorylated, whereas Ala substitutions reduced it, as evidenced by Western blotting, Elisa, and LDLR-immunolabeling. This newly uncovered PCSK9/LDLR regulation mechanism refines our understanding of the implication of global PCSK9 phosphorylation in the modulation of LDL-cholesterol and rationalizes the consequence of natural mutations, for example, S668R and E670G. Finally, the relationship of Ser-phosphorylation to the implication of PCSK9 in regulating LDL-cholesterol in the neurological Fragile X-syndrome disorder was investigated. Conclusions: Ser-phosphorylation of PCSK9 maximizes both its secretion and activity on the LDLR. Mass spectrometric approaches to measure such modifications were developed and applied to quantify the levels of bioactive PCSK9 in human plasma under normal and pathological conditions.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.119.313247
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1221433-4
    detail.hit.zdb_id: 1494427-3
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  • 10
    Online Resource
    Online Resource
    Role of protein phosphatases in the activation of CFTR (ABCC7) by genistein and bromotetramisole
    American Physiological Society ; 2000
    In:  American Journal of Physiology-Cell Physiology Vol. 279, No. 1 ( 2000-07-01), p. C108-C119
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 279, No. 1 ( 2000-07-01), p. C108-C119
    Abstract: Genistein and bromotetramisole (Br-t) strongly activate cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7) chloride channels on Chinese hamster ovary cells and human airway epithelial cells. We have examined the possible role of phosphatases in stimulation by these drugs using patch-clamp and biochemical methods. Genistein inhibited the spontaneous rundown of channel activity that occurs after membrane patches are excised from cAMP-stimulated cells but had no effect on purified protein phosphatase type 1 (PP1), PP2A, PP2B, PP2C, or endogenous phosphatases when assayed as [ 32 P]PO 4 release from prelabeled casein, recombinant GST-R domain fusion protein, or immunoprecipitated full-length CFTR. Br-t also slowed rundown of CFTR channels, but, in marked contrast to genistein, it did inhibit all four protein phosphatases tested. Half-maximal inhibition of PP2A and PP2C was observed with 0.5 and 1.5 mM Br-t, respectively. Protein phosphatases were also sensitive to (+)- p-Br-t, a stereoisomer of Br-t that does not inhibit alkaline phosphatases. Br-t appeared to act exclusively through phosphatases since it did not affect CFTR channels in patches that had low apparent endogenous phosphatase activity (i.e., those lacking spontaneous rundown). We conclude that genistein and Br-t act through different mechanisms. Genistein stimulates CFTR without inhibiting phosphatases, whereas Br-t acts by inhibiting a membrane-associated protein phosphatase (probably PP2C) that presumably allows basal phosphorylation to accumulate.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.2000.279.1.C108
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2000
    detail.hit.zdb_id: 1477334-X
    detail.hit.zdb_id: 392098-7
    SSG: 12
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