Classification of Human Solute Carrier Superfamily Members Reveals Functional Similarities across Families

Abstract

Solute Carrier (SLC) superfamily members are membrane transporter proteins that control the uptake and efflux of solutes, including essential cellular compounds, environmental toxins and therapeutic drugs, across biological membranes. Members of the SLC superfamily can share surprisingly similar structural features despite weak sequence similarities. Identification of sequence relationships among SLC members is needed to enhance our ability to model individual transporters and to elucidate the molecular mechanisms of their substrate specificity and transport. Here, we describe a comprehensive sequence-based classification of SLC members into families. We classify the proteins using sensitive profile-profile alignments and two classification approaches, including similarity networks. The clusters are analyzed in view of substrate specificity, transport mode, organism conservation, and tissue specificity. SLC families with similar substrates generally cluster together, despite exhibiting relatively weak sequence similarities. In contrast, some families cluster together with no apparent reason, revealing unexplored relationships. We demonstrate computationally and experimentally the functional overlap between representative members of these families. Finally, we identify 4 putative SLC transporters in the human genome. The SLC superfamily constitutes a biomedically important family of membrane proteins that is highly diverse in sequence. The proposed classification of the superfamily, combined with experiment, reveals new relationships among the individual families and identifies new superfamily members. The classification scheme will inform future attempts directed at modeling the structures of the SLC transporters, a prerequisite for describing their substrate specificity.