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, Kaspar P. Locher

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article number12100
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 Jul 14

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Alam, A., Woo, J. S., Schmitz, J., Prinz, B., Root, K., Chen, F., Bloch, J. S., Zenobi, R., & Locher, K. P. (2016). Structural basis of transcobalamin recognition by human CD320 receptor. Nature communications, 7, [12100]. https://doi.org/10.1038/ncomms12100