New insights into interactions between the nucleotide-binding domain of CFTR and keratin 8

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Details zur Publikation

Autor(en): Premchandar A, Kupniewska A, Bonna A, Faure G, Fraczyk T, Roldan A, Hoffmann B, Da Cunha MF, Herrmann H, Lukacs GL, Edelman A, Dadlez M
Zeitschrift: Protein Science
Jahr der Veröffentlichung: 2017
Band: 26
Heftnummer: 2
Seitenbereich: 343-354
ISSN: 0961-8368


Abstract


The intermediate filament protein keratin 8 (K8) interacts with the nucleotide-binding domain 1 (NBD1) of the cystic fibrosis (CF) transmembrane regulator (CFTR) with phenylalanine 508 deletion (?F508), and this interaction hampers the biogenesis of functional ?F508-CFTR and its insertion into the plasma membrane. Interruption of this interaction may constitute a new therapeutic target for CF patients bearing the ?F508 mutation. Here, we aimed to determine the binding surface between these two proteins, to facilitate the design of the interaction inhibitors. To identify the NBD1 fragments perturbed by the ?F508 mutation, we used hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS) on recombinant wild-type (wt) NBD1 and ?F508-NBD1 of CFTR. We then performed the same analysis in the presence of a peptide from the K8 head domain, and extended this investigation using bioinformatics procedures and surface plasmon resonance, which revealed regions affected by the peptide binding in both wt-NBD1 and ?F508-NBD1. Finally, we performed HDX-MS analysis of the NBD1 molecules and full-length K8, revealing hydrogen-bonding network changes accompanying complex formation. In conclusion, we have localized a region in the head segment of K8 that participates in its binding to NBD1. Our data also confirm the stronger binding of K8 to ?F508-NBD1, which is supported by an additional binding site located in the vicinity of the ?F508 mutation in NBD1.




Zusätzliche Organisationseinheit(en)
Neuropathologisches Institut


Autor(en) der externen Einrichtung(en)
Deutsches Krebsforschungszentrum (DKFZ)
Institut Pasteur
McGill University
Polska Akademia Nauk (PAN) / Polish Academy of Sciences
Universität Paris Descartes / Université Paris 5 René Descartes
Université Pierre et Marie Curie (UPMC, Sorbonne 6)


Zitierweisen

APA:
Premchandar, A., Kupniewska, A., Bonna, A., Faure, G., Fraczyk, T., Roldan, A.,... Dadlez, M. (2017). New insights into interactions between the nucleotide-binding domain of CFTR and keratin 8. Protein Science, 26(2), 343-354. https://dx.doi.org/10.1002/pro.3086

MLA:
Premchandar, Aiswarya, et al. "New insights into interactions between the nucleotide-binding domain of CFTR and keratin 8." Protein Science 26.2 (2017): 343-354.

BibTeX: 

Zuletzt aktualisiert 2018-06-10 um 03:05