7.6.2.8	evolution	ECF-transporters are multi-subunit membrane complexes that consist of two ATPases, similar to the ATPases of ABC transporters, and two membrane embedded proteins, not related to any other protein family	-, 750412	
7.6.2.8	evolution	Escherichia coli vitamin B12 transporter BtuCD-F is a type II importer and belongs to the ATP-binding cassette (ABC) transporter superfamily	751661	
7.6.2.8	evolution	the enzyme is a ABC transporter, all ABC-type ATPases encoded by the organism are predicted to be part of classical ABC transporters, and not ECF transporters. The organism does not encode an ECF-module. BtuM homologues (apart from one exception) are found exclusively in organisms lacking an ECF-module. But BtuMTd structurally resembles the S-components of ECF transporters	751670	
7.6.2.8	malfunction	ABCD4 dysfunction results in a failure of lysosomal vitamin B12 release	749821	
7.6.2.8	malfunction	gene disruption eliminates the ability of Mycobacterium tuberculosis to use exogenous vitamin B12 in vitro	734820	
7.6.2.8	malfunction	mutations in ABCD4 result in a failure to release vitamin B12 from lysosomes. A similar phenotype is caused by mutations in gene LMBRD1, which encodes the lysosomal membrane protein LMBD1. ABCD4 lysosomal localization is disturbed by knockout of LMBRD. Mutation of ABCD4, which is known as the cblJ complementation group, results in the failure of the release of cobalamin from lysosomes. A similar phenotype in patients within the cblF group is caused by mutations of LMBD1, a lysosomal membrane protein. Mistargeting of mutant LMBD1 affects the distribution of ABCD4. Thus, mutations of ABCD4 and LMBD1 result in a quite similar phenotype. A putative region of ABCD4 that interacts with LMBD1 might be masked by the exchange of the regions around transmembrane domains (TMs) 2 and 5	752200	
7.6.2.8	malfunction	substitution of W66 in BtuF with tyrosine or leucine reduced the affinity 3fold compared to wild-type, and a change to histidine or arginine reduces it more than 10fold	752221	
7.6.2.8	additional information	ABC importers follow the two-site access model3, in which ATP binding and hydrolysis switch the accessibility of the transmembrane domain for the substrate from an inward facing (accessible from the cytoplasm) to an outward-facing (accessible from the extracellular site) conformation, conformational changes by single-molecule FRET measurements combined with molecular dynamics simulations, two different transport cycles are analyzed	751644	
7.6.2.8	additional information	conformational coupling, molecular dynamics simulations using BtuCD-F is embedded in a solvated phosphatidylcholine bilayer, configurational entropy, pairwise residue-residue forces in BtuCD-F are analyzed through force distribution analysis, overview	750063	
7.6.2.8	additional information	function and structure of BtuMTd, cobalamin binding structure, overview	751670	
7.6.2.8	additional information	molecular dynamics simulation of structure of the cobalamin-binding protein BtuF compared to Escherichia coli BtuF structure	-, 749978	
7.6.2.8	additional information	post-hydrolysis state of the vitamin B12 importer BtuCD by molecular dynamics (MD) simulations, overview. Predominantly asymmetric arrangement of the NBD dimer interface, with the ADP-bound site disrupted and the ATP-bound site preserved in most of the trajectories. TMDs response to ATP hydrolysis by separation of the L-loops and opening of the cytoplasmic gate II, indicating that hydrolysis of one ATP facilitates substrate translocation by opening the cytoplasmic end of translocation pathway. Motions of the L-loops and the cytoplasmic gate II are coupled with each other through a contiguous interaction network involving a conserved Asn83 on the extended stretch preceding transmembrane (TM)3 helix plus the cytoplasmic end of TM2/6/7 helix bundle. TMD-NBD communication mechanism for type II ABC importers. Besides the four basic domains of BtuCD, a cognate periplasmic binding protein, BtuF, is also required to maximize transport rate. Different conformational states of BtuCD, and mechanism of B12 transport cycle in BtuCD, overview. The occluded state of BtuCD, occ-BtuCD (PDB ID 4FI3), is regarded as a crucial step of the transport cycle, in which the transporter simultaneously loads the shipment B12 and the energy source ATPs. Transition from the occ-BtuCD state to the inward-facing state after ATP hydrolysis	751956	
7.6.2.8	additional information	the crystal structure of cobinamide-bound BtuF reveals a conformational change of a tryptophan residue W66 in the substrate binding cleft compared to the structure of cobalamin-bound BtuF, molecular dynamics simulations. BtuF is a class III periplasmic substrate binding protein	752221	
7.6.2.8	additional information	the homodimer BtuC spans the membrane and the two identical cytosolic ATPase domains BtuD form a sandwich dimer that couple chemical energy of two ATP molecules into structural changes of the full complex. A single substrate-binding protein (SBP) completes the transporter. The SBP belongs to cluster A or class III and exhibits relatively small conformational changes upon substrate binding. Modeling of the transport mechanism of BtuCD-F transporters embedded in lipid bilayers at the single molecule level, overview	751661	
7.6.2.8	physiological function	ABCD4 is a transporter of cobalamin and forms a complex with LMBD1 for the proper targeting or functioning, or both. The two proteins function as a complex	752200	
7.6.2.8	physiological function	ABCD4 is located on lysosomal membrane and is involved in the transport of vitamin B12 from lysosomes to the cytosol	749821	
7.6.2.8	physiological function	ATP-binding cassette (ABC) transporters are a large family of integral membrane proteins and involved in nutrient uptake, drug extrusion, and lipid homeostasis. They use the energy of ATP binding and hydrolysis to power substrate transport across the lipid bilayer. BtuCD-F is an ABC transporter that mediates cobalamin (Cbl) uptake into Escherichia coli, Escherichia coli is unable to synthesize Cbl de novo. BtuCD-F might also be involved in the uptake of cobinamide, a cobalamin precursor. Precursor cobinamide (Cbi) lacks the 5,6-dimethylbenzimidazole (DMB) moiety and sugar-phosphate linker and is therefore smaller than Cbl. BtuCD-catalyzed in vitro transport of cyano-cobinamide is ATP- and BtuF-dependent. BtuF residue W66 is important for high affinity Cbi binding, but not for substrate delivery or transport	752221	
7.6.2.8	physiological function	ATP-binding cassette (ABC) transporters form the largest class of active membrane transport proteins. Binding and hydrolysis of ATP by their highly conserved nucleotide-binding domains drive conformational changes of the complex that mediate transport of substrate across the membrane. The transporter complex of vitamin B12 importer BtuCD-F from Escherichia coli is consisting of a periplasmic soluble binding protein BtuF that binds the ligand and the transmembrane and ATPase domains BtuCD mediating translocation	751661	
7.6.2.8	physiological function	bacterial ABC importers catalyze the uptake of essential nutrients including transition metals and metal-containing cofactors	752215	
7.6.2.8	physiological function	cobalamin-specific ECF-type ABC transporter from Lactobacillus delbrueckii, ECF-CbrT, mediates the specific, ATP-dependent uptake of cobalamin. Cobalamin (vitamin B12) is the most complex B-type vitamin and is synthetized exclusively in a limited number of prokaryotes. Its biologically active variants contain rare organometallic bonds, which are used by enzymes in a variety of central metabolic pathways such as L-methionine synthesis and ribonucleotide reduction. Enzyme ECF-CbrT catalyzes ATP-dependent transport of cobalamin and cobinamide	-, 750412	
7.6.2.8	physiological function	the ABC transporter BtuCD-F imports vitamin B12 across the inner membrane of Escherichia coli. Substrate translocation by ATP-binding cassette (ABC) transporters involves coupling of ATP binding and hydrolysis in the nucleotide-binding domains (NBDs) to conformational changes in the transmembrane domains	750063	
7.6.2.8	physiological function	the ATP-binding cassette (ABC) importer family catalyzse the uptake of nutrients, vitamins and trace elements. Membrane transport proteins generally are inherently flexible and undergo substantial conformational changes to catalyze the translocation of their substrates across biological membranes. The vitamin B12 import system BtuCD-F from Escherichia coli shows the conformational dynamics during the transport cycle	751644	
7.6.2.8	physiological function	the enzyme is required for the assimilation of exogenous vitamin B12 to enable methylmalonyl-CoA pathway function and is essential for corrinoid transport	734820	
7.6.2.8	physiological function	the membrane protein BtuM acts as transporter for uptake of essential vitamin B12, i.e. cobalamin, one of the most complex cofactors known, and used by enzymes catalyzing for instance methyl-group transfer and ribonucleotide reduction reactions. BtuMTd likely combines two functions: transport of the substrate into the bacterial cell, and chemical modification of the substrate. A cobalt-cysteine interaction allows for chemical modification of the substrate prior to translocation, which is a rare feature among uptake systems. BtuM homologues are small membrane proteins of about 22 kDa, and found predominantly in Gram-negative species, distributed mostly over alpha-, beta-, and gamma-proteobacteria	751670	
7.6.2.8	physiological function	vitamin B12 importer BtuCD is a type II ATP binding cassette (ABC) importer mediating the uptake of vitamin B12 across the inner membrane. ABC transporters utilize the energy of ATP hydrolysis to unidirectionally transport substrates across cell membrane. ATP hydrolysis occurs at the nucleotide-binding domain (NBD) dimer interface of ABC transporters, whereas substrate translocation takes place at the translocation pathway between the transmembrane domains (TMDs), which is more than 30 A away from the NBD dimer interface	751956