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

Content Provider	Journal of Biological Chemistry (JBC)
Author	Benoit, Courtney R. Stanton, Abigail E. Tartanian, Aileen C. Motzer, Andrew R. McGaughey, David M. Bond, Stephen R. Brody, Lawrence C.
Abstract	In humans, transport of food-derived cobalamin (vitamin B12) 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 α-domain and a β-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 α-domain. These β-domain–only 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.
Related Links	http://www.jbc.org/content/293/45/17606.abstract
Ending Page	17621
Starting Page	17606
Page Count	16
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	45
Volume Number	293
DOI	10.1074/jbc.RA118.005323
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2018-11-09
Access Restriction	Open
Subject Keyword	Zebrafish One-carbon metabolism Transport Phylogenetics Protein evolution Affinity Cobalamin Transcobalamin Vitamin B12 Molecular Bases of Disease
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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