open access publication

Article, 2024

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

Nature Communications, ISSN 2041-1723, Volume 15, 1, Page 4380, 10.1038/s41467-024-48569-7

Contributors

Yee, Sook Wah 0000-0001-8121-8746 [1] Ferrández-Peral, Luis 0000-0003-0338-0603 [2] Alentorn-Moron, Pol 0000-0002-4858-0652 [2] Fontsere, Claudia 0000-0003-2233-6026 [2] [3] Ceylan, Merve [4] Koleske, Megan L 0000-0002-9826-6442 [1] Handin, Niklas [4] Artegoitia, Virginia M [5] Lara, Giovanni 0009-0004-6706-0945 [1] Chien, Huan-Chieh [1] Zhou, Xujia 0000-0003-2491-0933 [1] Dainat, Jacques [6] Zalevsky, Arthur O 0000-0001-6987-8119 [1] Sali, Andrej [1] Brand, Colin M [1] Wolfreys, Finn D 0000-0003-1057-633X [1] Yang, Jia [1] Gestwicki, Jason Edward [1] Capra, John Anthony [1] Artursson, Per [4] Newman, John William 0000-0001-9632-6571 [5] [7] Marques-Bonet, Tomas 0000-0002-5597-3075 [2] [8] [9] [10] Giacomini, Kathleen M (Corresponding author) [1]

Affiliations

  1. [1] University of California, San Francisco
    2. [NORA names: United States; America, North; OECD];
  2. [2] Institute of Evolutionary Biology
    3. [NORA names: Spain; Europe, EU; OECD];
  3. [3] University of Copenhagen
    4. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  4. [4] Uppsala University
    5. [NORA names: Sweden; Europe, EU; Nordic; OECD];
  5. [5] Western Human Nutrition Research Center
    6. [NORA names: United States; America, North; OECD];

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.

Keywords

Denisovan genomes, Denisovans, SLC22A10, accumulation, alignment, apes, biological role, cells, characteristics, conjugate, development, evolution, fluorescent protein, function, functional characteristics, functional loss, genome, goal, green fluorescent protein, homeostasis, hominin evolution, hominins, humans, leucine, localization, loss, membrane, membrane localization, missense, missense mutations, mutations, organ development, organization, orphan, orphan transporters, orthologs, p220, plasma, plasma membrane, plasma membrane localization, primates, proline, protein, pseudogenes, role, sequence, sequence alignment, species, specificity, steroid conjugates, steroid homeostasis, steroids, study, substrate, substrate specificity, transport, uptake, uptake function

Funders

  • European Research Council
  • Government of Catalonia
  • Swedish Research Council
  • United States Department of Agriculture
  • National Eye Institute
  • European Union
  • National Institute of General Medical Sciences
  • European Commission

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