The crystal structure of human holo-transcobalamin reveals a two-domain architecture with one cobalamin buried in base-on conformation at the domain interface, defining the structural basis of cobalamin binding.

The transcobalamin-2 cDNA encodes an 18-residue leader peptide and a secreted 409-residue protein; the protein is a plasma cobalamin-binding protein secreted by endothelial cells and mediates cellular uptake of cobalamin.

The holo-TC:CD320 co-crystal structure shows transcobalamin-2, carrying bound cobalamin, engaging the LDLR-A domains of the cell-surface receptor CD320, the interaction that drives receptor-mediated cellular uptake of vitamin B12; binding is Ca2+-dependent and reduced at endosomal (low) pH.

Transcobalamin-2 was purified from human plasma as a secreted holo-protein containing one cobalamin per protein molecule, establishing its extracellular localization and 1:1 cobalamin binding.

Recombinant transcobalamin-2 is constitutively secreted, binds cobalamin, and facilitates cobalamin uptake into cells by binding the plasma-membrane TCII-Cbl receptor, directly demonstrating its cobalamin-binding and transport functions.

UniProt describes transcobalamin-2 as the primary vitamin B12-binding and transport protein that delivers cobalamin to cells, is secreted, and interacts with CD320 via its LDL-receptor class A domains; loss of function causes transcobalamin II deficiency (TCN2D).