Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates
Open accessPreprint — published as 10.1038/s41467-024-48569-7 · Paper page
Abstract
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.
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- Authors
- Giacomini, K., Yee, S. W., Ferrández-Peral, L., Alentorn, P., Fontsere, C., Ceylan, M., Koleske, M., Handin, N., Artegoitia, V., Lara, G., Chien, H.-C., Zhou, X., Dainat, J., Zalevsky, A., Sali, A., Brand, C., Capra, J., Artursson, P., Newman, J., & Marques-Bonet, T.
- Affiliations
- University of California, San Francisco (US)
- Institut de Biologia Evolutiva (ES)
- Institute of Evolutionary Biology (UPF-CSIC)
- University of Copenhagen (DK)
- Uppsala University (SE)
- United States Department of Agriculture (US)
- Université de Montpellier (FR)
- University of California, San Francisco
- Agricultural Research Service (US)
- Institut de Biologia Evolutiva (CSIC/Universitat Pompeu Fabra) / CNAG (Centro de Analisis Genomico) PCB
- Corresponding author
- Giacomini, Kathleen
- ORCID
- Venue
- Research Square
- Published
- 2023-09-14
- PMC
- PMC10543398
- OpenAlex
- W4386738203
- Cited by
- 1
- References
- 3
- Citations by year
- 2025: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- Funders
- U.S. Department of Agriculture (2032‐51530‐025‐00D)
- Centres de Recerca de Catalunya
- European Commission (864203, HORIZON2020)
- Generalitat de Catalunya (864203)
- National Institutes of Health (-0001)
- National Institute of General Medical Sciences (R01GM139875, R01GM117163)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- orphan transporter, estradiol-17β-glucuronide, substrate specificity, plasma membrane localization, Neanderthal genome, pseudogenes, missense mutations, hominin evolution, primate evolution
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