Structural basis of transcobalamin recognition by human CD320 receptor

Amer Alam, Jae-Sung Woo, Jennifer Schmitz, Bernadette Prinz, Katharina Root, Fan Chen, Joël S. Bloch, Renato Zenobi and Kaspar P. Locher ()
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Amer Alam: Institute of Molecular Biology and Biophysics, ETH Zurich
Jae-Sung Woo: Institute of Molecular Biology and Biophysics, ETH Zurich
Jennifer Schmitz: Institute of Molecular Biology and Biophysics, ETH Zurich
Bernadette Prinz: Institute of Molecular Biology and Biophysics, ETH Zurich
Katharina Root: ETH Zurich
Fan Chen: ETH Zurich
Joël S. Bloch: Institute of Molecular Biology and Biophysics, ETH Zurich
Renato Zenobi: ETH Zurich
Kaspar P. Locher: Institute of Molecular Biology and Biophysics, ETH Zurich

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract Cellular uptake of vitamin B12 (cobalamin) requires capture of transcobalamin (TC) from the plasma by CD320, a ubiquitous cell surface receptor of the LDLR family. Here we present the crystal structure of human holo-TC in complex with the extracellular domain of CD320, visualizing the structural basis of the TC-CD320 interaction. The observed interaction chemistry can rationalize the high affinity of CD320 for TC and lack of haptocorrin binding. The in vitro affinity and complex stability of TC-CD320 were quantitated using a solid-phase binding assay and thermostability analysis. Stable complexes with TC were also observed for the disease-causing CD320ΔE88 mutant and for the isolated LDLR-A2 domain. We also determined the structure of the TC-CD320ΔE88 complex, which revealed only minor changes compared with the wild-type complex. Finally, we demonstrate significantly reduced in vitro affinity of TC for CD320 at low pH, recapitulating the proposed ligand release during the endocytic pathway.

Date: 2016
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DOI: 10.1038/ncomms12100

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