Show simple item record

dc.contributor.authorRuggiero, Melissa J.
dc.contributor.authorMalhotra, Shipra
dc.contributor.authorFenton, Aron W.
dc.contributor.authorSwint-Kruse, Liskin
dc.contributor.authorKaranicolas, John
dc.contributor.authorHagenbuch, Bruno
dc.date.accessioned2022-01-06T19:51:35Z
dc.date.available2022-01-06T19:51:35Z
dc.date.issued2020-11-09
dc.identifier.citationRuggiero, 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.RA120.014889en_US
dc.identifier.urihttp://hdl.handle.net/1808/32357
dc.description.abstractConventionally, 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.publisherElsevieren_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.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectBile acid transporten_US
dc.subjectDrug transporten_US
dc.subjectSingle nucleotide polymorphismen_US
dc.subjectHepatocyteen_US
dc.subjectLiveren_US
dc.subjectProtein stabilityen_US
dc.titleA clinically relevant polymorphism in the Na+/taurocholate cotransporting polypeptide (NTCP) occurs at a rheostat positionen_US
dc.typeArticleen_US
kusw.kuauthorMalhotra, Shipra
kusw.kudepartmentCenter for Computational Biologyen_US
dc.identifier.doi10.1074/jbc.RA120.014889en_US
dc.identifier.orcidhttps://orcid.org/ 0000-0002-2234-191Xen_US
dc.identifier.orcidhttps://orcid.org/ 0000-0001-8214-4785en_US
dc.identifier.orcidhttps://orcid.org/ 0000-0002-5925-9741en_US
dc.identifier.orcidhttps://orcid.org/ 0000-0003-0300-726Xen_US
dc.identifier.orcidhttps://orcid.org/ 0000-0002-2938-8630en_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7948949en_US
dc.rights.accessrightsopenAccessen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

© 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.
Except where otherwise noted, this item's license is described as: © 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.