ATTENTION: The software behind KU ScholarWorks is being upgraded to a new version. Starting July 15th, users will not be able to log in to the system, add items, nor make any changes until the new version is in place at the end of July. Searching for articles and opening files will continue to work while the system is being updated.
If you have any questions, please contact Marianne Reed at mreed@ku.edu .
A clinically relevant polymorphism in the Na+/taurocholate cotransporting polypeptide (NTCP) occurs at a rheostat position
dc.contributor.author | Ruggiero, Melissa J. | |
dc.contributor.author | Malhotra, Shipra | |
dc.contributor.author | Fenton, Aron W. | |
dc.contributor.author | Swint-Kruse, Liskin | |
dc.contributor.author | Karanicolas, John | |
dc.contributor.author | Hagenbuch, Bruno | |
dc.date.accessioned | 2022-01-06T19:51:35Z | |
dc.date.available | 2022-01-06T19:51:35Z | |
dc.date.issued | 2020-11-09 | |
dc.identifier.citation | Ruggiero, M. J., Malhotra, S., Fenton, A. W., Swint-Kruse, L., Karanicolas, J., & Hagenbuch, B. (2021). A clinically relevant polymorphism in the Na+/taurocholate cotransporting polypeptide (NTCP) occurs at a rheostat position. The Journal of biological chemistry, 296, 100047. https://doi.org/10.1074/jbc.RA120.014889 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/32357 | |
dc.description.abstract | Conventionally, most amino acid substitutions at “important” protein positions are expected to abolish function. However, in several soluble-globular proteins, we identified a class of nonconserved positions for which various substitutions produced progressive functional changes; we consider these evolutionary “rheostats”. Here, we report a strong rheostat position in the integral membrane protein, Na+/taurocholate (TCA) cotransporting polypeptide, at the site of a pharmacologically relevant polymorphism (S267F). Functional studies were performed for all 20 substitutions (S267X) with three substrates (TCA, estrone-3-sulfate, and rosuvastatin). The S267X set showed strong rheostatic effects on overall transport, and individual substitutions showed varied effects on transport kinetics (Km and Vmax) and substrate specificity. To assess protein stability, we measured surface expression and used the Rosetta software (https://www.rosettacommons.org) suite to model structure and stability changes of S267X. Although buried near the substrate-binding site, S267X substitutions were easily accommodated in the Na+/TCA cotransporting polypeptide structure model. Across the modest range of changes, calculated stabilities correlated with surface-expression differences, but neither parameter correlated with altered transport. Thus, substitutions at rheostat position 267 had wide-ranging effects on the phenotype of this integral membrane protein. We further propose that polymorphic positions in other proteins might be locations of rheostat positions. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | © 2020 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC-BY license. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Bile acid transport | en_US |
dc.subject | Drug transport | en_US |
dc.subject | Single nucleotide polymorphism | en_US |
dc.subject | Hepatocyte | en_US |
dc.subject | Liver | en_US |
dc.subject | Protein stability | en_US |
dc.title | A clinically relevant polymorphism in the Na+/taurocholate cotransporting polypeptide (NTCP) occurs at a rheostat position | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Malhotra, Shipra | |
kusw.kudepartment | Center for Computational Biology | en_US |
dc.identifier.doi | 10.1074/jbc.RA120.014889 | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0002-2234-191X | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0001-8214-4785 | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0002-5925-9741 | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0003-0300-726X | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0002-2938-8630 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7948949 | en_US |
dc.rights.accessrights | openAccess | en_US |