Systematic in silico discovery of novel solute carrier-like proteins from proteomes

Abstract

Solute carrier (SLC) proteins represent the largest superfamily of transmembrane transporters, the systematic analysis of which is hampered by their functional and structural heterogeneity, despite their biological importance. Based on available nomenclature systems, we suspected that many as yet unidentified SLC transporters exist in the human genome. Here, we present criteria for defining “SLC-likeness” and apply them to curate a set of “SLC-like” protein families from the Transporter Classification Database (TCDB) and Protein families (Pfam) databases. Computational sequence similarity searches then surprisingly yielded ∼130 more proteins in human with SLC-like properties, compared to previous annotations. Several of these novel putative SLC transporter proteins actually have documented transport activity in the scientific literature. We complete our overview of the SLC-ome by presenting an algorithm to classify SLC-like proteins into protein families, investigating their known functions and evolutionary relationships to similar proteins from 6 other clinically relevant experimental organisms, and pinpointing structural orphans. We envision that our work will serve as a stepping stone for future studies of the biological function and the identification of the natural substrates of the many under-explored SLC transporters, as well as the development of new therapeutic applications, including strategies for personalized medicine and drug delivery.