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

Nat Commun. 2024 May 23;15(1):4380. doi: 10.1038/s41467-024-48569-7.

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Estradiol / metabolism
  • HEK293 Cells
  • Hominidae / genetics
  • Hominidae / metabolism
  • Humans
  • Mutation, Missense
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • Primates* / genetics
  • Pseudogenes
  • Substrate Specificity

Substances

  • Estradiol
  • Organic Cation Transport Proteins
  • SLC22A10 protein, human