Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12100
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Funding
- Swiss Cancer League [KFS 3004-08-2012]
- NCCR TransCure
- Swiss National Science Foundation [SNF 200020-124663, SNF 31003A_146191, SNF 310030B_166672]
- European Molecular Biology Organization (EMBO) [ALTF-770-2010]
- Swiss National Science Foundation (SNF) [31003A_146191] Funding Source: Swiss National Science Foundation (SNF)
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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 CD320DE88 mutant and for the isolated LDLR-A2 domain. We also determined the structure of the TC-CD320DE88 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.
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