Structure of the human transcobalamin beta domain in four distinct states

Bloch, J.S.; Ruetz, Markus; Kräutler, Bernhard; Locher, Kaspar P.

doi:10.1371/journal.pone.0184932

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…S2 B ). The way the α-and β-domains accommodate Cbl is in agreement with the observation that association of α/β-domain in Cbl transporters is Cbl-dependent and that isolated α- and β-domains have the ability to bind Cbl ( 22 , 23 , 24 ). For example, there are organisms that have only the β-domain as B 12 transport proteins ( 25 ).…”

Section: Resultssupporting

confidence: 87%

“…Even though there is a substantial buried surface area between the α- and β-domain, Cbl is required for α- and β-domain association in Cbl transporters ( 22 , 23 ). Cbl binds sequentially to the β-domain of Cbl transporters and then the α-domain closes onto the β-domain–Cbl complex ( 22 , 23 , 24 , 35 ), which is consistent with PISA analysis.…”

Section: Resultsmentioning

confidence: 99%

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The structure of the rat vitamin B12 transporter TC and its complex with glutathionylcobalamin

Bokhove,

Kawamura,

Okumura

et al. 2024

Journal of Biological Chemistry

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

The structure of the rat vitamin B12 transporter TC and its complex with glutathionylcobalamin

Bokhove,

Kawamura,

Okumura

et al. 2024

Journal of Biological Chemistry

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“…, was able to bind cobalamin independently, albeit several orders of magnitude less avidly than the full-length form, IF 50 (K d Յ1 pM) (46). In a more recent study, the crystal structure of the ␤-domain of human TC in complex with cyanocobalamin was solved, thereby demonstrating the ability of the ␤-domain to bind cobalamin in the absence of the ␣-domain (47).…”

Section: Noncanonical Vitamin B 12 -Binding Proteins In Zebrafishmentioning

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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“…Each fasta sequence of every gene of the operon comprised between lsa1836 and lsa1840 was retrieved from UnitProtKB server at http://www.uniprot.org/uniprot, uploaded then analyzed using HHpred server (44) that detects structural homologues. For Lsa1839 and Lsa1840, that partly shares strong structural homology with Geranyl-geranyltransferase type-I (pdb id 5nsa, chain A) (51), and β domain of human haptocorrin (pdb id 4kki chain A) (52), intrinsic factor with cobalamin (pdb id 2pmv) (53) and transcobalamin (pdb id 2bb6 chainA) (54) respectively, homology modeling was performed using Modeler, version Mod9v18 (55). The heterodimer was then formed with respect to the functional and structural assembly of α and β domains of the native haptocorrin (52).…”

Section: Methodsmentioning

confidence: 99%

Heme uptake inLactobacillus sakeievidenced by a new ECF-like transport system

Verplaetse

André-Leroux

Duhutrel

et al. 2019

Preprint

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19Lactobacillus sakei is a non-pathogenic lactic acid bacterium and a natural inhabitant of meat 20 ecosystems. Although red meat is a heme-rich environment, L. sakei does not need iron or 21 heme for growth, while possessing a heme-dependent catalase. Iron incorporation into L. 22 sakei from myoglobin and hemoglobin was formerly shown by microscopy and the L. sakei 23 genome reveals a complete equipment for iron and heme transport. Here, we report the 24 characterization of a five-gene cluster (lsa1836-1840) encoding a putative metal iron ABC 25 transporter. Interestingly, this cluster, together with a heme dependent catalase gene, is also 26 conserved in other species from the meat ecosystem. Our bioinformatic analyses revealed 27 that the locus might refer to a complete machinery of an Energy Coupling Factor (ECF) 28 transport system. We quantified in vitro the intracellular heme in wild-type (WT) and in our 29Dlsa1836-1840 deletion mutant using an intracellular heme sensor and ICP-Mass 30 spectrometry for quantifying incorporated 57 Fe heme. We showed that in the WT L. sakei, 31 heme accumulation occurs fast and massively in the presence of hemin, while the deletion 32 mutant was impaired in heme uptake; this ability was restored by in trans complementation. 33 Our results establish the main role of the L. sakei Lsa1836-1840 ECF-like system in heme 34 uptake. This research outcome shed new light on other possible functions of ECF-like 35 systems. 36 37 38 Importance 39Lactobacillus sakei is a non-pathogenic bacterial species exhibiting high fitness in heme rich 40 environments such as meat products, although it does not need iron nor heme for growth. 41Heme capture and utilization capacities are often associated with pathogenic species and are 42 considered as virulence-associated factors in the infected hosts. For these reasons, iron 43 3 acquisition systems have been deeply studied in such species, while for non-pathogenic 44 bacteria the information is scarce. Genomic data revealed that several putative iron 45 transporters are present in the genome of the lactic acid bacterium L. sakei. In this study, we 46 demonstrate that one of them, is an ECF-like ABC transporter with a functional role in heme 47 transport. Such evidence has not yet been brought for an ECF, therefore our study reveals a 48 new class of heme transport system. 49 50 51 7 It was evidenced that ECF transporters constitute a novel family of conserved membrane 126 transporters in prokaryotes, while sharing a similar four domains organization as the ABC 127 transporters. Each ECF displays a pair of cytosolic nucleotide-binding ATPases (the A and A' 128 components also called EcfA and EcfA'), a membrane-embedded substrate-binding protein 129 (the S component or the EcfS), and a transmembrane energy-coupling component (The T 130 component or EcfT). The quadripartite organization has a 1:1:1:1 stoichiometry. Notably, the 131 S component renders ECF mechanistically distinct from ABC transport systems as it is 132 predicted to shuttle within the ...

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Structure of the human transcobalamin beta domain in four distinct states

Cited by 7 publications

References 32 publications

The structure of the rat vitamin B12 transporter TC and its complex with glutathionylcobalamin

The structure of the rat vitamin B12 transporter TC and its complex with glutathionylcobalamin

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

Heme uptake inLactobacillus sakeievidenced by a new ECF-like transport system

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