Functional diversification of sea urchin ABCC1 (MRP1) by alternative splicing

Am J Physiol Cell Physiol. 2016 Jun 1;310(11):C911-20. doi: 10.1152/ajpcell.00029.2016. Epub 2016 Apr 6.

Abstract

The multidrug resistance protein (MRP) family encodes a diverse repertoire of ATP-binding cassette (ABC) transporters with multiple roles in development, disease, and homeostasis. Understanding MRP evolution is central to unraveling their roles in these diverse processes. Sea urchins occupy an important phylogenetic position for understanding the evolution of vertebrate proteins and have been an important invertebrate model system for study of ABC transporters. We used phylogenetic analyses to examine the evolution of MRP transporters and functional approaches to identify functional forms of sea urchin MRP1 (also known as SpABCC1). SpABCC1, the only MRP homolog in sea urchins, is co-orthologous to human MRP1, MRP3, and MRP6 (ABCC1, ABCC3, and ABCC6) transporters. However, efflux assays revealed that alternative splicing of exon 22, a region critical for substrate interactions, could diversify functions of sea urchin MRP1. Phylogenetic comparisons also indicate that while MRP1, MRP3, and MRP6 transporters potentially arose from a single transporter in basal deuterostomes, alternative splicing appears to have been the major mode of functional diversification in invertebrates, while duplication may have served a more important role in vertebrates. These results provide a deeper understanding of the evolutionary origins of MRP transporters and the potential mechanisms used to diversify their functions in different groups of animals.

Keywords: ATP-binding cassette transporters; development; multidrug resistance protein 1 (also known as ABCC1); protein evolution; sea urchin.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing*
  • Animals
  • Biological Transport
  • Evolution, Molecular*
  • Exons
  • Fluoresceins / metabolism
  • Fluorescent Dyes / metabolism
  • Gene Duplication
  • Multidrug Resistance-Associated Proteins / genetics*
  • Multidrug Resistance-Associated Proteins / metabolism
  • Phylogeny
  • Sea Urchins / genetics*
  • Sea Urchins / metabolism

Substances

  • Fluoresceins
  • Fluorescent Dyes
  • Multidrug Resistance-Associated Proteins
  • 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester
  • 5-chloromethylfluorescein
  • calcein AM
  • multidrug resistance-associated protein 1