A Single Rainbow Trout Cobalamin-binding Protein Stands in for Three Human Binders

Greibe, Eva; Fedosov, Sergey N.; Sørensen, Boe Sandahl; Højrup, Peter; Poulsen, Steen Seier; Nexø, Ebba

doi:10.1074/jbc.m112.398016

Cited by 12 publications

(8 citation statements)

References 31 publications

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“…Interestingly, in species lacking HC, including mice and lower vertebrates, a TC-like protein has been shown to be less specific for Cbl and to recognize Cbi and other corrinoids, similar to human HC (32)(33)(34). According to the sequence alignment (Figs.…”

Section: Discussionmentioning

confidence: 99%

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

Furger¹,

Frei

Schibli

et al. 2013

Journal of Biological Chemistry

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Background: Haptocorrin (HC) is a cobalamin (Cbl) transport protein known to recognize a wide range of corrinoids. Results: We solved the crystal structure of human HC in complex with Cbl and cobinamide. Conclusion: HC recognizes corrinoids by establishing distinct contacts with the corrin ring. Significance: Our findings complete the molecular details for corrinoid recognition by human Cbl transport proteins.

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Section: Discussionmentioning

confidence: 99%

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

Furger¹,

Frei

Schibli

et al. 2013

Journal of Biological Chemistry

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“…Furthermore, it has been theorized that one of the two paralogs resulting from 2R was then lost in the teleost lineage (infraclass of the ray-finned fish Actinopterygii), whereas a tandem duplication further expanded that gene into HC and IF in the ancestor of Sarcopterygii (the lobe-finned fish, which are ancestral to Tetrapoda and therefore all land-dwelling vertebrates) (18). This resulted in one and three predicted cobalamin-carrier proteins in these lineages, respectively (20,21). HC is proposed to have been secondarily lost in amphibians, birds, and some mammalian species (18).…”

mentioning

confidence: 99%

Functional and phylogenetic characterization of noncanonical vitamin B12–binding proteins in zebrafish suggests involvement in cobalamin transport

Benoit

Stanton

Tartanian

et al. 2018

Journal of Biological Chemistry

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Edited by Ruma Banerjee In humans, transport of food-derived cobalamin (vitamin B 12) from the digestive system into the bloodstream involves three paralogous proteins: transcobalamin (TC), haptocorrin (HC), and intrinsic factor (IF). Each of these proteins contains two domains, an ␣-domain and a ␤-domain, which together form a cleft in which cobalamin binds. Zebrafish (Danio rerio) are thought to possess only a single cobalamin transport protein, referred to as Tcn2, which is a transcobalamin homolog. Here, we used CRISPR/Cas9 mutagenesis to create null alleles of tcn2 in zebrafish. Fish homozygous for tcn2-null alleles were viable and exhibited no obvious developmentally or behaviorally abnormal phenotypes. For this reason, we hypothesized that previously unidentified cobalamin-carrier proteins encoded in the zebrafish genome may provide an additional pathway for cobalamin transport. We identified genes predicted to code for two such proteins, Tcn-beta-a (Tcnba) and Tcn-beta-b (Tcnbb), which differ from all previously characterized cobalamin transport proteins as they lack the ␣-domain. These ␤-domainonly proteins are representative of an undescribed class of cobalamin-carrier proteins that are highly conserved throughout the ray-finned fishes. We observed that the genes encoding the three cobalamin transport homologs, tcn2, tcnba, and tcnbb, are expressed in unique spatial and temporal patterns in the developing zebrafish. Moreover, exogenously expressed recombinant Tcnba and Tcnbb bound cobalamin with high affinity, comparable with binding by full-length Tcn2. Taken together, our results suggest that this noncanonical protein structure has evolved to fully function as a cobalamin-carrier protein, thereby allowing for a compensatory cobalamin transport mechanism in the tcn2 ؊/؊ zebrafish. Vitamin B 12 , also referred to as cobalamin, is a micronutrient that acts as a cofactor for two enzymes: methionine synthase, This article contains Figs. S1-S4 and Table S1.

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“…When compared with the other carriers, TCN1 exhibits higher binding affinity toward Cbl, faster binding kinetics, and lower specificity, binding other apparently inert corrinoids ( Fedosov et al 2007 ; Wuerges et al 2007 ). In the lumen of the upper gut, TCN1 confers increased stability to the carrier-corrinoid complex at low pH conditions; yet, due to its reduced resistance to pancreatic proteolytic enzymes Cbl is relayed to GIF in the small intestine ( Greibe, Fedosov, Sorensen, et al 2012 ). Although TCN1 also binds the vast majority of Cbl in the plasma, its role there is more elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Structurally it resembles a hybrid of the full set of human Cbl binders. The sequence identity is closer to Tcn2 ( Greibe, Fedosov, Nexø, et al 2012 ), the amino acid composition at the binding site is similar to Tcn1 ( Greibe, Fedosov, Nexø, et al 2012 ; Greibe, Fedosov, Sorensen, et al 2012 ), and it shows resistance toward degradation by trypsin comparable to Gif ( Greibe, Fedosov, Nexø, et al 2012 ; Greibe, Fedosov, Sorensen, et al 2012 ). Consequently, it has been named HIT (an abbreviation for haptocorrin, intrinsic factor, and transcobalamin) denoting its intermediate and ancestral nature ( Greibe, Fedosov, Nexø, et al 2012 ).…”

Section: Introductionmentioning

confidence: 89%

“…In birds and amphibians two binders have been found, whereas in reptiles a similar gene repertoire to that of most mammals is found ( Greibe, Fedosov, Nexø, et al 2012 ). Teleosts such as zebrafish, trout, and salmon have a single documented binder ( Greibe, Fedosov, Nexø, et al 2012 ; Greibe, Fedosov, Sorensen, et al 2012 ). This has led to the proposal that the evolutionary elaboration of Cbl binding proteins occurred “after” the divergence of Actinopterygians ( Greibe, Fedosov, Nexø, et al 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Basal Gnathostomes Provide Unique Insights into the Evolution of Vitamin B12 Binders

Lopes-Marques

Ruivo

Delgado

et al. 2014

Genome Biology and Evolution

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The uptake and transport of vitamin B12 (cobalamin; Cbl) in mammals involves a refined system with three evolutionarily related transporters: transcobalamin 1 (Tcn1), transcobalamin 2 (Tcn2), and the gastric intrinsic factor (Gif). Teleosts have a single documented binder with intermediate features to the human counterparts. Consequently, it has been proposed that the expansion of Cbl binders occurred after the separation of Actinopterygians. Here, we demonstrate that the diversification of this gene family took place earlier in gnathostome ancestry. Our data indicates the presence of single copy orthologs of the Sarcopterygii/Tetrapoda duplicates Tcn1 and Gif, and Tcn2, in Chondrichthyes. In addition, a highly divergent Cbl binder was found in the Elasmobranchii. We unveil a complex scenario forged by genome, tandem duplications and lineage-specific gene loss. Our findings suggest that from an ancestral transporter, exhibiting large spectrum and high affinity binding, highly specific Cbl transporters emerged through gene duplication and mutations at the binding pocket.

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A Single Rainbow Trout Cobalamin-binding Protein Stands in for Three Human Binders

Cited by 12 publications

References 31 publications

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

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

Functional and phylogenetic characterization of noncanonical vitamin B12–binding proteins in zebrafish suggests involvement in cobalamin transport

Basal Gnathostomes Provide Unique Insights into the Evolution of Vitamin B12 Binders

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