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Structural basis of transcobalamin recognition by human CD320 receptor

Author

Listed:
  • 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)

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.

Suggested Citation

  • Amer Alam & Jae-Sung Woo & Jennifer Schmitz & Bernadette Prinz & Katharina Root & Fan Chen & Joël S. Bloch & Renato Zenobi & Kaspar P. Locher, 2016. "Structural basis of transcobalamin recognition by human CD320 receptor," Nature Communications, Nature, vol. 7(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12100
    DOI: 10.1038/ncomms12100
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