Ligand Similarity Complements Sequence, Physical Interaction, and Co-Expression for Gene Function Prediction
(A) A schematic of glutamate signaling showing three of the major types of proteins involved—ionotropic glutamate receptors, metabotropic glutamate receptors, and glutamate transporters. (B) Proteins annotated in IUPHAR as involved in glutamatergic neurotransmission and linked by ligand-based SEA E-values better than 1e-25. (C) Proteins annotated in IUPHAR as involved in glutamatergic neurotransmission and linked by human physical protein-protein interactions from BioGRID (v3.2.121). (D) The ligand-similarity and PPI networks from (B) and (C) merged and extended to adjacent related proteins, using (1) ligand-based (orange edges, using a SEA E-value threshold of 1e-75), (2) protein-protein interactions restricting to those supported by at least one low-throughput observation, one physical observation, and observed in at least two different experiments (green edges), and (3) co-expression links at a 94% threshold (pink edges). Edges that overlapped between shared nodes from the independent networks shown in (B) and (C), calculated at less stringent cut-offs, are preserved here to illustrate the few cases of overlap between the networks (e.g., between GRIA1 and GRIA2).