Structural informatic study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants

Solute carrier transporters are integral membrane proteins, and are important for diverse cellular nutrient transports, metabolism, energy demand, and other vital biological activities. They have recently been implicated in pancreatic cancer and other cancer metastasis, angiogenesis, programmed cell death and proliferation, cell metabolism and chemo-sensitivity. Here we report the study of 13 human solute carrier membrane transporters using the highly accurate AlphaFold2 predictions of 3D protein structures. In the native structures, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F) in the transmembrane alpha-helices. These hydrophobic amino acids L, I, V, F are systematically replaced by hydrophilic amino acids glutamine (Q), threonine (T) and tyrosine (Y), thus the QTY code. Therefore, these QTY variant transporters become water-soluble without requiring detergents. We present the superposed structures of these native solute carrier transporters and their water-soluble QTY variants. The superposed structures show remarkable similarity with RMSD similar to 1 angstrom-< 3 angstrom despite > 46% protein sequence substitutions in transmembrane alpha-helices. We also show the differences of surface hydrophobicity between the native solute carrier transporters and their QTY variants. Our study may further stimulate designs of water-soluble transmembrane proteins and other aggregated proteins for drug discovery and biotechnological applications.

Automated summary

Solute carrier transporters play vital roles in cellular nutrient transports and other biological activities. In this study, we used AlphaFold2 to predict the 3D structures of 13 human solute carrier transporters and discovered that hydrophobic amino acid substitutions can make these transporters water-soluble. Our findings have implications in the design of water-soluble transmembrane proteins.