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PMID:27411955

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Citation

Alam, A, Woo, JS, Schmitz, J, Prinz, B, Root, K, Chen, F, Bloch, JS, Zenobi, R and Locher, KP (2016) Structural basis of transcobalamin recognition by human CD320 receptor. Nat Commun 7:12100

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.

Links

PubMed PMC4947154 Online version:10.1038/ncomms12100

Keywords

Antigens, CD/chemistry; Antigens, CD/metabolism; Crystallography, X-Ray; Histidine/metabolism; Humans; Hydrogen-Ion Concentration; Models, Molecular; Protein Domains; Structure-Activity Relationship; Transcobalamins/chemistry; Transcobalamins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TCO2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPF0

F

Seeded From UniProt

complete

HUMAN:CD320

enables

GO:0005509: calcium ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CD320

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20062

F

Seeded From UniProt

complete

HUMAN:TCO2

enables

GO:0031419: cobalamin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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