Structural Basis for Universal Corrinoid Recognition by the Cobalamin Transport Protein Haptocorrin

Furger, Evelyne; Frei, D.C.; Schibli, Roger; Fischer, Eliane; Prota, A.E.

doi:10.1074/jbc.m113.483271

Cited by 40 publications

(39 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The three human Cbl‐binding proteins TC, IF, and HC show considerable homology of their primary sequences and have the same general topology, as shown by recent crystallographic analyses of rhTC, hrIF, and rhHC . The holoproteins contain two well‐structured units (an amino‐terminal α domain with largely α‐helix elements, and the C‐terminal β domain with mostly β sheets) connected by a peptide linker.…”

Section: Discussionmentioning

confidence: 78%

See 1 more Smart Citation

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

et al. 2017

View full text Add to dashboard Cite

The synthesis and structural characterization of Co-(dN) -Cbl (Cbl: cobalamin; dN: deoxynucleotide) and Co-(dN) -Cbl, which are organometallic DNA-B conjugates with single DNA strands consisting of 25 and 39 deoxynucleotides, respectively, and binding studies of these two DNA-Cbl conjugates to three homologous human Cbl transporting proteins, transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are reported. This investigation tests the suitability of such DNA-Cbls for the task of eventual in vivo oligonucleotide delivery. The binding of DNA-Cbl to TC, IF, and HC was investigated in competition with either a fluorescent Cbl derivative and Co-(dN) -Cbl, or radiolabeled vitamin B ( Co-CNCbl) and Co-(dN) -Cbl or Co-(dN) -Cbl. Binding of the new DNA-Cbl conjugates was fast and tight with TC, but poorer with HC and IF, which extends a similar original finding with the simpler DNA-Cbl, Co-(dN) -Cbl. The contrasting affinities of TC versus IF and HC for the DNA-Cbl conjugates are rationalized herein by a stepwise mechanism of Cbl binding. Critical contributions to overall affinity result from gradual conformational adaptations of the Cbl-binding proteins to the DNA-Cbl, which is first bound to the respective β domains. This transition is fast with TC, but slow with IF and HC, with which weaker binding results. The invariably tight interaction of the DNA-Cbl conjugates with TC makes the Cbl moiety a potential natural vector for the specific delivery of oligonucleotide loads from the blood into cells.

show abstract

Section: Discussionmentioning

confidence: 78%

“…The structured α and β domains of holo‐TC, holo‐IF, and holo‐HC recognize Cbl through interactions at the periphery of the corrin ligand . Solvent‐accessible areas of the bound Cbl ligands are found at the upper coordination site of Cbl, in particular.…”

Section: Discussionmentioning

confidence: 99%

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

et al. 2017

View full text Add to dashboard Cite

show abstract

“…transporting holo-proteins (Cbl@HC, Cbl@IF, Cbl@TCII; see chapter 1.2),2,39,53,[118][119][120][121][122] The studies suggest modifications at the 5`-OH moiety of the ribose unit and at the cobalt centre of Cbls as best suited for developing B 12 -conjugates for diagnosis and therapy 15,53. Interestingly, these particular points of modifications have already been earlier suggested when analysing the binding of biotin modified Cbls to TCII 123.…”

mentioning

confidence: 94%

Recent trends in the development of vitamin B₁₂derivatives for medicinal applications

Zelder

2015

Chem. Commun.

View full text Add to dashboard Cite

This Feature Article highlights recent developments in the field of vitamin B12 derivatives for medicinal applications. The following topics are emphasized: (1) the development of aquacorrinoids for cyanide detection and detoxification, (2) the use of vitamin B12 conjugates and (3) antivitamins B12 for therapy and diagnosis, and (4) the design of corrinoids as activators of soluble guanylyl cyclase (sGC).

show abstract

“…Although most vitamin B-12 is bound to haptocorrin, TCbound vitamin B-12 is delivered to the liver and other tissues where it is taken up by a TC receptor protein (23)(24)(25). The physiologic role of haptocorrin in circulation remains unclear, although haptocorrin may act as a scavenger protein to remove inactive vitamin B-12 analogs from circulation (26,27).…”

Section: Introductionmentioning

confidence: 99%

Vitamin B-12 and Perinatal Health

Finkelstein

Layden

Stover

2015

Advances in Nutrition

133

104

View full text Add to dashboard Cite

Vitamin B-12 deficiency (<148 pmol/L) is associated with adverse maternal and neonatal outcomes, including developmental anomalies, spontaneous abortions, preeclampsia, and low birth weight (<2500 g). The importance of adequate vitamin B-12 status periconceptionally and during pregnancy cannot be overemphasized, given its fundamental role in neural myelination, brain development, and growth. Infants born to vitamin B-12-deficient women may be at increased risk of neural tube closure defects, and maternal vitamin B-12 insufficiency (<200 pmol/L) can impair infant growth, psychomotor function, and brain development, which may be irreversible. However, the underlying causal mechanisms are unknown. This review was conducted to examine the evidence that links maternal vitamin B-12 status and perinatal outcomes. Despite the high prevalence of vitamin B-12 deficiency and associated risk of pregnancy complications, few prospective studies and, to our knowledge, only 1 randomized trial have examined the effects of vitamin B-12 supplementation during pregnancy. The role of vitamin B-12 in the etiology of adverse perinatal outcomes needs to be elucidated to inform public health interventions. Adv Nutr 2015;6:552-63.

show abstract

Structural Basis for Universal Corrinoid Recognition by the Cobalamin Transport Protein Haptocorrin

Cited by 40 publications

References 34 publications

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Recent trends in the development of vitamin B₁₂derivatives for medicinal applications

Vitamin B-12 and Perinatal Health

Contact Info

Product

Resources

About

Structural Basis for Universal Corrinoid Recognition by the Cobalamin Transport Protein Haptocorrin

Cited by 40 publications

References 34 publications

Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Organometallic DNA–B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Recent trends in the development of vitamin B12derivatives for medicinal applications

Vitamin B-12 and Perinatal Health

Contact Info

Product

Resources

About

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Organometallic DNA–B₁₂ Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin‐Transport Proteins

Recent trends in the development of vitamin B₁₂derivatives for medicinal applications