Summary: B12 binding domain
This is the Wikipedia entry entitled "Vitamin B12-binding domain". More...
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Vitamin B12-binding domain Edit Wikipedia article
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nmr structure of glutamate mutase (b12-binding subunit) complexed with the vitamin b12 nucleotide
|B12-binding_2 (4-helical bundle cap domain)|
how a protein binds b12: a 3.o angstrom x-ray structure of the b12-binding domains of methionine synthase
In molecular biology, the vitamin B12-binding domain is a protein domain which binds to cobalamin (vitamin B12). It can bind two different forms of the cobalamin cofactor, with cobalt bonded either to a methyl group (methylcobalamin) or to 5'-deoxyadenosine (adenosylcobalamin). Cobalamin-binding domains are mainly found in two families of enzymes present in animals and prokaryotes, which perform distinct kinds of reactions at the cobalt-carbon bond. Enzymes that require methylcobalamin carry out methyl transfer reactions. Enzymes that require adenosylcobalamin catalyse reactions in which the first step is the cleavage of adenosylcobalamin to form cob(II)alamin and the 5'-deoxyadenosyl radical, and thus act as radical generators. In both types of enzymes the B12-binding domain uses a histidine to bind the cobalt atom of cobalamin cofactors. This histidine is embedded in a DXHXXG sequence, the most conserved primary sequence motif of the domain. Proteins containing the cobalamin-binding domain include:
- Animal and prokaryotic methionine synthase (EC 220.127.116.11), which catalyse the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine.
- Animal and prokaryotic methylmalonyl-CoA mutase (EC 18.104.22.168), which are involved in the degradation of several amino acids, odd-chain fatty acids and cholesterol via propionyl-CoA to the tricarboxylic acid cycle.
The core structure of the cobalamin-binding domain is characterised by a five-stranded alpha/beta (Rossmann) fold, which consists of 5 parallel beta-sheets surrounded by 4-5 alpha helices in three layers (alpha/beta/alpha). Upon binding cobalamin, important elements of the binding site appear to become structured, including an alpha-helix that forms on one side of the cleft accommodating the nucleotide 'tail' of the cofactor. In cobalamin, the cobalt atom can be either free (dmb-off) or bound to dimethylbenzimidazole (dmb-on) according to the pH. When bound to the cobalamin-binding domain, the dimethylbenzimidazole ligand is replaced by the active histidine (His-on) of the DXHXXG motif. The replacement of dimethylbenzimidazole by histidine allows switching between the catalytic and activation cycles. In methionine synthase the cobalamin cofactor is sandwiched between the cobalamin-binding domain and an approximately 90 residues N-terminal domain forming a helical bundle comprising two pairs of antiparallel helices. This N-terminal domain forms a 4-helical bundle cap, in the conversion to the active conformation of this enzyme, the 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain.
- Krautler B (August 2005). "Vitamin B12: chemistry and biochemistry". Biochem. Soc. Trans. 33 (Pt 4): 806–10. doi:10.1042/BST0330806. PMID 16042603.
- Ludwig ML, Matthews RG (1997). "Structure-based perspectives on B12-dependent enzymes". Annu. Rev. Biochem. 66: 269–313. doi:10.1146/annurev.biochem.66.1.269. PMID 9242908.
- Banerjee R, Ragsdale SW (2003). "The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes". Annu. Rev. Biochem. 72: 209–47. doi:10.1146/annurev.biochem.72.121801.161828. PMID 14527323.
- Reitzer R, Gruber K, Jogl G, Wagner UG, Bothe H, Buckel W, Kratky C (August 1999). "Glutamate mutase from Clostridium cochlearium: the structure of a coenzyme B12-dependent enzyme provides new mechanistic insights". Structure 7 (8): 891–902. doi:10.1016/s0969-2126(99)80116-6. PMID 10467146.
- Drennan CL, Huang S, Drummond JT, Matthews RG, Lidwig ML (December 1994). "How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase". Science 266 (5191): 1669–74. doi:10.1126/science.7992050. PMID 7992050.
- Mancia F, Keep NH, Nakagawa A, Leadlay PF, McSweeney S, Rasmussen B, BÃ¶secke P, Diat O, Evans PR (March 1996). "How coenzyme B12 radicals are generated: the crystal structure of methylmalonyl-coenzyme A mutase at 2 A resolution". Structure 4 (3): 339–50. doi:10.1016/s0969-2126(96)00037-8. PMID 8805541.
- Bandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML (January 2002). "Domain alternation switches B(12)-dependent methionine synthase to the activation conformation". Nat. Struct. Biol. 9 (1): 53–6. doi:10.1038/nsb738. PMID 11731805.
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B12 binding domain Provide feedback
This B12 binding domain is found in methionine synthase EC:22.214.171.124 Q99707 and other shorter proteins that bind to B12. This domain is always found to the N-terminus of PF02310. The structure of this domain is known  it is a 4 helix bundle. Many of the conserved residues in this domain are involved in B12 binding, such as those in the MXXVG motif.
Drennan CL, Huang S, Drummond JT, Matthews RG, Lidwig ML; , Science 1994;266:1669-1674.: How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase PUBMED:7992050 EPMC:7992050
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR003759
Cobalamin-dependent methionine synthase (EC) is a large modular protein that catalyses methyl transfer from methyltetrahydrofolate (CH3-H4folate) to homocysteine. During the catalytic cycle, it supports three distinct methyl transfer reactions, each involving the cobalamin (vitamin B12) cofactor and a substrate bound to its own functional unit [PUBMED:11731805]. The cobalamin cofactor plays an essential role in this reaction, accepting the methyl group from CH3-H4folate to form methylcob(III)alamin, and in turn donating the methyl group to homocysteine to generate methionine and cob(I)alamin.
Methionine synthase is a large enzyme composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and CH3-H4folate, the third module binds the cobalamin cofactor and the C-terminal module binds S-adenosylmethionine. The cobalamin-binding module is composed of two structurally distinct domains: a 4-helical bundle cap domain (residues 651-740 in the Escherichia coli enzyme) and an alpha/beta B12-binding domain (residues 741-896) (INTERPRO). The 4-helical bundle forms a cap over the alpha/beta domain, which acts to shield the methyl ligand of cobalamin from solvent [PUBMED:8939751]. Furthermore, in the conversion to the active conformation of this enzyme, the 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain (INTERPRO). The alpha/beta domain is a common cobalamin-binding motif, whereas the 4-helical bundle domain with its methyl cap is a distinctive feature of methionine synthases.
This entry represents the 4-helical bundle cap domain. This domain is also present in other shorter proteins that bind to B12, and is always found N terminus to the alpha/beta B12-binding domain.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||metal ion binding (GO:0046872)|
|cobalamin binding (GO:0031419)|
|methionine synthase activity (GO:0008705)|
|Biological process||methionine biosynthetic process (GO:0009086)|
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Curation and family details
|Seed source:||Bateman A|
|Author:||Bateman A, Eberhardt R|
|Number in seed:||255|
|Number in full:||3838|
|Average length of the domain:||78.30 aa|
|Average identity of full alignment:||34 %|
|Average coverage of the sequence by the domain:||9.66 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the B12-binding_2 domain has been found. There are 16 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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