Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates

Sook Wah Yee, Luis Ferrández-Peral, Pol Alentorn-Moron, Claudia Fontsere, Merve Ceylan, Megan L. Koleske, Niklas Handin, Virginia M. Artegoitia, Giovanni Lara, Huan-Chieh Chien, Xujia Zhou, Jacques Dainat, Arthur Zalevsky, Andrej Sali, Colin M. Brand, Finn D. Wolfreys, Jia Yang, Jason E. Gestwicki, John A. Capra, Per Artursson, John W. Newman, Tomàs Marquès-Bonet and Kathleen M. Giacomini ()
Additional contact information
Sook Wah Yee: University of California
Luis Ferrández-Peral: Dr. Aiguader 88
Pol Alentorn-Moron: Dr. Aiguader 88
Claudia Fontsere: Dr. Aiguader 88
Merve Ceylan: Uppsala University
Megan L. Koleske: University of California
Niklas Handin: Uppsala University
Virginia M. Artegoitia: Western Human Nutrition Research Center
Giovanni Lara: University of California
Huan-Chieh Chien: University of California
Xujia Zhou: University of California
Jacques Dainat: BP 64501
Arthur Zalevsky: University of California
Andrej Sali: University of California
Colin M. Brand: University of California
Finn D. Wolfreys: University of California
Jia Yang: University of California
Jason E. Gestwicki: University of California
John A. Capra: University of California
Per Artursson: Uppsala University
John W. Newman: Western Human Nutrition Research Center
Tomàs Marquès-Bonet: Dr. Aiguader 88
Kathleen M. Giacomini: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.

Date: 2024
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DOI: 10.1038/s41467-024-48569-7

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