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Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences
ABCG2 is an ABC (ATP-binding cassette) transporter with a physiological role in urate transport in the kidney and is also implicated in multi-drug efflux from a number of organs in the body. The trafficking of the protein and the mechanism by which it recognizes and transports diverse drugs are impo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613716/ https://www.ncbi.nlm.nih.gov/pubmed/26294421 http://dx.doi.org/10.1042/BSR20150150 |
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author | Haider, Ameena J. Cox, Megan H. Jones, Natalie Goode, Alice J. Bridge, Katherine S. Wong, Kelvin Briggs, Deborah Kerr, Ian D. |
author_facet | Haider, Ameena J. Cox, Megan H. Jones, Natalie Goode, Alice J. Bridge, Katherine S. Wong, Kelvin Briggs, Deborah Kerr, Ian D. |
author_sort | Haider, Ameena J. |
collection | PubMed |
description | ABCG2 is an ABC (ATP-binding cassette) transporter with a physiological role in urate transport in the kidney and is also implicated in multi-drug efflux from a number of organs in the body. The trafficking of the protein and the mechanism by which it recognizes and transports diverse drugs are important areas of research. In the current study, we have made a series of single amino acid mutations in ABCG2 on the basis of sequence analysis. Mutant isoforms were characterized for cell surface expression and function. One mutant (I573A) showed disrupted glycosylation and reduced trafficking kinetics. In contrast with many ABC transporter folding mutations which appear to be ‘rescued’ by chemical chaperones or low temperature incubation, the I573A mutation was not enriched at the cell surface by either treatment, with the majority of the protein being retained in the endoplasmic reticulum (ER). Two other mutations (P485A and M549A) showed distinct effects on transport of ABCG2 substrates reinforcing the role of TM helix 3 in drug recognition and transport and indicating the presence of intracellular coupling regions in ABCG2. |
format | Online Article Text |
id | pubmed-4613716 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-46137162015-11-02 Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences Haider, Ameena J. Cox, Megan H. Jones, Natalie Goode, Alice J. Bridge, Katherine S. Wong, Kelvin Briggs, Deborah Kerr, Ian D. Biosci Rep Original Papers ABCG2 is an ABC (ATP-binding cassette) transporter with a physiological role in urate transport in the kidney and is also implicated in multi-drug efflux from a number of organs in the body. The trafficking of the protein and the mechanism by which it recognizes and transports diverse drugs are important areas of research. In the current study, we have made a series of single amino acid mutations in ABCG2 on the basis of sequence analysis. Mutant isoforms were characterized for cell surface expression and function. One mutant (I573A) showed disrupted glycosylation and reduced trafficking kinetics. In contrast with many ABC transporter folding mutations which appear to be ‘rescued’ by chemical chaperones or low temperature incubation, the I573A mutation was not enriched at the cell surface by either treatment, with the majority of the protein being retained in the endoplasmic reticulum (ER). Two other mutations (P485A and M549A) showed distinct effects on transport of ABCG2 substrates reinforcing the role of TM helix 3 in drug recognition and transport and indicating the presence of intracellular coupling regions in ABCG2. Portland Press Ltd. 2015-08-20 /pmc/articles/PMC4613716/ /pubmed/26294421 http://dx.doi.org/10.1042/BSR20150150 Text en © 2015 Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0 (http://creativecommons.org/licenses/by/3.0/) . |
spellingShingle | Original Papers Haider, Ameena J. Cox, Megan H. Jones, Natalie Goode, Alice J. Bridge, Katherine S. Wong, Kelvin Briggs, Deborah Kerr, Ian D. Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences |
title | Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences |
title_full | Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences |
title_fullStr | Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences |
title_full_unstemmed | Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences |
title_short | Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences |
title_sort | identification of residues in abcg2 affecting protein trafficking and drug transport, using co-evolutionary analysis of abcg sequences |
topic | Original Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613716/ https://www.ncbi.nlm.nih.gov/pubmed/26294421 http://dx.doi.org/10.1042/BSR20150150 |
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