# The structure of the rat vitamin B12 transporter TC and its complex with glutathionylcobalamin

## TL;DR

This study reveals that the vitamin B12 transporter TC can bind and transport glutathionylcobalamin, a form of vitamin B12, and that this ability is conserved across species.

## Contribution

The first crystallographic evidence that TC can bind GSCbl and that this binding is conserved among TCs from different organisms.

## Key findings

- TC binds GSCbl as effectively as aquo/hydroxocobalamin.
- The residues involved in GSCbl binding are conserved across TCs from different species.
- Haptocorrin and intrinsic factor do not bind GSCbl.

## Abstract

Vitamin B12 (cobalamin or Cbl) functions as a cofactor in two important enzymatic processes in human cells, and life is not sustainable without it. B12 is obtained from food and travels from the stomach, through the intestine, and into the bloodstream by three B12-transporting proteins: salivary haptocorrin (HC), gastric intrinsic factor, and transcobalamin (TC), which all bind B12 with high affinity and require proteolytic degradation to liberate Cbl. After intracellular delivery of dietary B12, Cbl in the aquo/hydroxocobalamin form can coordinate various nucleophiles, for example, GSH, giving rise to glutathionylcobalamin (GSCbl), a naturally occurring form of vitamin B12. Currently, there is no data showing whether GSCbl is recognized and transported in the human body. Our crystallographic data shows for the first time the complex between a vitamin B12 transporter and GSCbl, which compared to aquo/hydroxocobalamin, binds TC equally well. Furthermore, sequence analysis and structural comparisons show that TC recognizes and transports GSCbl and that the residues involved are conserved among TCs from different organisms. Interestingly, haptocorrin and intrinsic factor are not structurally tailored to bind GSCbl. This study provides new insights into the interactions between TC and Cbl.