Comparison of human solute carriers

Abstract

Solute carriers are eukaryotic membrane proteins that control the uptake and efflux of solutes, including essential cellular compounds, environmental toxins, and therapeutic drugs. Solute carriers can share similar structural features despite weak sequence similarities. Identification of sequence relationships among solute carriers is needed to enhance our ability to model individual carriers and to elucidate the molecular mechanisms of their substrate specificity and transport. Here, we describe a comprehensive comparison of solute carriers. We link the proteins using sensitive profile-profile alignments and two classification approaches, including similarity networks. The clusters are analyzed in view of substrate type, transport mode, organism conservation, and tissue specificity. Solute carrier 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 four putative solute carriers in the human genome. The solute carriers include a biomedically important group of membrane proteins that is diverse in sequence and structure. The proposed classification of solute carriers, combined with experiment, reveals new relationships among the individual families and identifies new solute carriers. The classification scheme will inform future attempts directed at modeling the structures of the solute carriers, a prerequisite for describing the substrate specificities of the individual families.

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

“…T he transport of solute across membranes is crucial to eukaryotic cell physiology, as illustrated in the human species by the existence of diverse diseases associated with defective transport (1-3) and the presence of ∼400 solute transporter genes grouped into 51 families in the human genome (www.bioparadigms.org/slc/ menu.asp) (4,5). However, this inventory is far from being complete, because the function of many putative transporters remains unknown and, for technical reasons, the repertoire of elucidated activities is biased in favor of cellular uptake at the expense of less tractable activities, such as cellular export or intracellular solute compartmentalization.…”

Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET

“…Because of the difficulty of determining atomic structures of membrane proteins, structures of transporters, particularly from human, are not well represented in the Protein Data Bank (PDB) (46). However, in the past few years, structures of several prokaryotic and eukaryotic membrane transporters have been determined at atomic resolution (47,48). Despite relatively low sequence similarity between these structures and their human homologs with unknown structures, some of these structures can serve as templates for constructing useful models (47).…”

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