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Volume 22
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10.3390/ijms22136910
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Article

Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model

by
Flora Szeri
1,2,
Valentina Corradi
3,
Fatemeh Niaziorimi
1,
Sylvia Donnelly
1,
Gwenaëlle Conseil
4,
Susan P. C. Cole
4,
D. Peter Tieleman
3 and
Koen van de Wetering
1,*
1
Department of Dermatology and Cutaneous Biology and PXE Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA 19107, USA
2
Research Centre for Natural Sciences, Institute of Enzymology, 1117 Budapest, Hungary
3
Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, AB T2N 1N4, Canada
4
Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(13), 6910; https://doi.org/10.3390/ijms22136910
Submission received: 8 May 2021 / Revised: 19 June 2021 / Accepted: 23 June 2021 / Published: 27 June 2021
(This article belongs to the Special Issue ABC Transporters in Human Diseases)
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Abstract

Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site.
Keywords: ABC transporter; pseudoxanthoma elasticum; homology modeling; substrate-binding site; cellular ATP efflux; mutagenesis ABC transporter; pseudoxanthoma elasticum; homology modeling; substrate-binding site; cellular ATP efflux; mutagenesis

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MDPI and ACS Style

Szeri, F.; Corradi, V.; Niaziorimi, F.; Donnelly, S.; Conseil, G.; Cole, S.P.C.; Tieleman, D.P.; van de Wetering, K. Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model. Int. J. Mol. Sci. 2021, 22, 6910. https://doi.org/10.3390/ijms22136910

AMA Style

Szeri F, Corradi V, Niaziorimi F, Donnelly S, Conseil G, Cole SPC, Tieleman DP, van de Wetering K. Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model. International Journal of Molecular Sciences. 2021; 22(13):6910. https://doi.org/10.3390/ijms22136910

Chicago/Turabian Style

Szeri, Flora, Valentina Corradi, Fatemeh Niaziorimi, Sylvia Donnelly, Gwenaëlle Conseil, Susan P. C. Cole, D. Peter Tieleman, and Koen van de Wetering. 2021. "Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model" International Journal of Molecular Sciences 22, no. 13: 6910. https://doi.org/10.3390/ijms22136910

APA Style

Szeri, F., Corradi, V., Niaziorimi, F., Donnelly, S., Conseil, G., Cole, S. P. C., Tieleman, D. P., & van de Wetering, K. (2021). Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model. International Journal of Molecular Sciences, 22(13), 6910. https://doi.org/10.3390/ijms22136910

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