Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.

Autor: Yee SW; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA., Ferrández-Peral L; Institute of Evolutionary Biology (UPF-CSIC), PRBB, 08003 Barcelona, Spain., Alentorn P; Institute of Evolutionary Biology (UPF-CSIC), PRBB, 08003 Barcelona, Spain., Fontsere C; Institute of Evolutionary Biology (UPF-CSIC), PRBB, 08003 Barcelona, Spain; Center for Evolutionary Hologenomics, The Globe Institute, University of Copenhagen, Øster Farimagsgade 5A, 1352 Copenhagen, Denmark., Ceylan M; Department of Pharmacy and Science for Life Laboratory, Uppsala University, P.O. Box 580, 75123, Uppsala, Sweden., Koleske ML; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA., Handin N; Department of Pharmacy and Science for Life Laboratory, Uppsala University, P.O. Box 580, 75123, Uppsala, Sweden., Artegoitia VM; United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616, USA., Lara G; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA., Chien HC; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA., Zhou X; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA., Dainat J; Joint Research Unit for Infectious Diseases and Vectors Ecology Genetics Evolution and Control (MIVEGEC), University of Montpellier, French National Center for Scientific Research (CNRS 5290), French National Research Institute for Sustainable Development (IRD 224), 911 Avenue Agropolis, BP 64501, 34394 Montpellier Cedex 5, France., Zalevsky A; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA., Sali A; Department of Bioengineering and Therapeutic Sciences, UCSF Box 0775 1700 4th St, University of California, San Francisco, San Francisco, CA 94158, United States; Department of Pharmaceutical Chemistry, University of California, San Francisco, UCSF Box 2880 600 16th St, San Francisco, CA 94143, United States; Quantitative Biosciences Institute (QBI), University of California, San Francisco, 1700 4th St, San Francisco, CA, United States., Brand CM; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA., Capra JA; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA., Artursson P; Department of Pharmacy and Science for Life Laboratory, Uppsala University, P.O. Box 580, 75123, Uppsala, Sweden., Newman JW; United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616, USA; Department of Nutrition, University of California, Davis, Davis, CA 95616, USA; UC Davis West Coast Metabolomics Center, Davis, CA 95616, USA., Marques-Bonet T; Institute of Evolutionary Biology (UPF-CSIC), PRBB, 08003 Barcelona, Spain; Institute of Evolutionary Biology (UPF-CSIC), PRBB, Dr. Aiguader 88, 08003 Barcelona, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Passeig de Lluís Companys, 23, 08010, Barcelona, Spain; CNAG, Centro Nacional de Analisis Genomico, Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain; Institut Català de Paleontologia Miquel Crusafont, Universitat Autònoma de Barcelona, Edifici ICTA-ICP, c/ Columnes s/n, 08193 Cerdanyola del Vallès, Barcelona, Spain., Giacomini KM; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2023 Sep 14. Date of Electronic Publication: 2023 Sep 14.
DOI: 10.21203/rs.3.rs-3263845/v1
Abstrakt: SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17β-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.
Databáze: MEDLINE