TBC1D

TBC1D refers to a family of proteins that contain a Tre-2/Bub2/Cdc16 (TBC) Rab GTPase-activating domain, collectively known as the TBC1 domain-containing (TBC1D) family. Members act as Rab GTPase-activating proteins (GAPs), accelerating GTP hydrolysis on specific Rab GTPases and thereby inactivating Rab signaling to regulate vesicle formation, trafficking, and fusion. The TBC1D family is part of the larger TBC superfamily and is expressed in a variety of tissues across vertebrates. Many family members harbor additional motifs that influence localization and interactions with other trafficking proteins.

Function and regulation of activity are often linked to cellular signaling. Rab GAP activity of TBC1D proteins is frequently regulated by phosphorylation through kinases such as Akt and AMPK, which can modulate GAP activity, subcellular distribution, and responses to insulin, energy status, or growth signals. This regulatory versatility enables TBC1D proteins to coordinate trafficking events with metabolic and signaling cues.

Examples and roles within humans include TBC1D1, TBC1D2, TBC1D3, TBC1D4 (also known as AS160), and TBC1D5. TBC1D4 AS160 has been studied for its role in insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane. TBC1D1 is implicated in energy metabolism and muscle glucose uptake. Other TBC1D proteins participate in endosomal and lysosomal trafficking and may influence neuronal transport, reflecting the diversity of Rab pathways regulated by the family.

Genomics and evolution of TBC1D domain proteins show a conserved core across eukaryotes, with lineage-specific expansions in different groups. In vertebrates, multiple TBC1D genes have diversified to regulate distinct Rab pathways, illustrating how the TBC1D domain functions as a modular Rab GAP module in cellular trafficking networks.