|SMART accession number:||SM00094|
|Interpro abstract (IPR001156):|
Transferrins are eukaryotic iron-binding glycoproteins that control the level of free iron in biological fluids [(PUBMED:3032619)]. The proteins have arisen by duplication of a domain, each duplicated domain binding one iron atom. Members of the family include blood serotransferrin (siderophilin); milk lactotransferrin (lactoferrin); egg white ovotransferrin (conalbumin); and membrane-associated melanotransferrin.
Additional members of this family include inhibitor of carbonic anhydrase (ICA; mammals), major yolk protein (sea urchins), saxiphilin (frog), pacifastin (crayfish), and TTF-1 (algae). Most family members contain two transferrin-like domains of around 340 amino acids, the result of an ancient duplication event [(PUBMED:15621505)]. Each of the duplicated domains can be further divided into two subdomains that form a cleft inside of which the iron atom is bound in iron-transporting transferrin [(PUBMED:2585506)]. The iron-coordinating residues consist of an aspartic acid, two tyrosines and a histidine, as well as an arginine that coordinates a requisite anion. In addition to iron and anion liganding residues, the transferrin-like domain contains conserved cysteine residues involved in disulphide bond formation.
Human lactoferrin is a serine peptidase belonging to MEROPS peptidase family S60, clan SR. It is found at high concentrations in all human secretions, where it plays a major role in mucosal defence. Lactoferrin cleaves IgA1 protease at an arginine-rich region defined by amino acids RRSRRSVR and digests Hap at a similar arginine-rich sequence (VRSRRAAR). Ser259 and Lys73 form a catalytic dyad, reminiscent of a number of bacterial serine proteases.
|GO process:||cellular iron ion homeostasis (GO:0006879), iron ion transport (GO:0006826)|
|GO component:||extracellular region (GO:0005576)|
|GO function:||ferric iron binding (GO:0008199)|
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- Evolution (species in which this domain is found)
Click on to expand nodes. To display all proteins with a TR_FER domain in a specific node, click on it.
This tree shows only several representative species. The complete taxonomic breakdown of all proteins with TR_FER domain is also avaliable.
- Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Anderson BF, Baker HM, Norris GE, Rice DW, Baker EN
- Structure of human lactoferrin: crystallographic structure analysis and refinement at 2.8 A resolution.
- J Mol Biol. 1989; 209: 711-34
- Display abstract
The structure of human lactoferrin has been refined crystallographically at 2.8 A (1 A = 0.1 nm) resolution using restrained least squares methods. The starting model was derived from a 3.2 A map phased by multiple isomorphous replacement with solvent flattening. Rebuilding during refinement made extensive use of these experimental phases, in combination with phases calculated from the partial model. The present model, which includes 681 of the 691 amino acid residues, two Fe3+, and two CO3(2-), gives an R factor of 0.206 for 17,266 observed reflections between 10 and 2.8 A resolution, with a root-mean-square deviation from standard bond lengths of 0.03 A. As a result of the refinement, two single-residue insertions and one 13-residue deletion have been made in the amino acid sequence, and details of the secondary structure and tertiary interactions have been clarified. The two lobes of the molecule, representing the N-terminal and C-terminal halves, have very similar folding, with a root-mean-square deviation, after superposition, of 1.32 A for 285 out of 330 C alpha atoms; the only major differences being in surface loops. Each lobe is subdivided into two dissimilar alpha/beta domains, one based on a six-stranded mixed beta-sheet, the other on a five-stranded mixed beta-sheet, with the iron site in the interdomain cleft. The two iron sites appear identical at the present resolution. Each iron atom is coordinated to four protein ligands, 2 Tyr, 1 Asp, 1 His, and the specific Co3(2-), which appears to bind to iron in a bidentate mode. The anion occupies a pocket between the iron and two positively charged groups on the protein, an arginine side-chain and the N terminus of helix 5, and may serve to neutralize this positive charge prior to iron binding. A large internal cavity, beyond the Arg side-chain, may account for the binding of larger anions as substitutes for CO3(2-). Residues on the other side of the iron site, near the interdomain crossover strands could provide secondary anion binding sites, and may explain the greater acid-stability of iron binding by lactoferrin, compared with serum transferrin. Interdomain and interlobe interactions, the roles of charged side-chains, heavy-atom binding sites, and the construction of the metal site in relation to the binding of different metals are also discussed.
- Crichton RR, Charloteaux-Wauters M
- Iron transport and storage.
- Eur J Biochem. 1987; 164: 485-506
- Disease (disease genes where sequence variants are found in this domain)
SwissProt sequences and OMIM curated human diseases associated with missense mutations within the TR_FER domain.
Protein Disease Serotransferrin (P02787) (SMART) OMIM:190000: Atransferrinemia
- Structure (3D structures containing this domain)
3D Structures of TR_FER domains in PDB
PDB code Main view Title 1a8e Human serum transferrin, recombinant n-terminal lobe 1a8f Human serum transferrin, recombinant n-terminal lobe 1aiv Apo ovotransferrin 1aov Apo duck ovotransferrin 1b0l Recombinant human diferric lactoferrin 1b1x Structure of diferric mare lactoferrin at 2.62a resolution 1b3e Human serum transferrin, n-terminal lobe, expressed in pichia pastoris 1b7u Structure of mare apolactoferrin: the n and c lobes are in the closed form 1b7z Structure of oxalate substituted diferric mare lactoferrin from colostrum 1biy Structure of diferric buffalo lactoferrin 1bka Oxalate-substituted diferric lactoferrin 1blf Structure of diferric bovine lactoferrin at 2.8 angstroms resolution 1bp5 Human serum transferrin, recombinant n-terminal lobe, apo form 1btj Human serum transferrin, recombinant n-terminal lobe, apo form, crystal form 2 1cb6 Structure of human apolactoferrin at 2.0 a resolution. 1ce2 Structure of diferric buffalo lactoferrin at 2.5a resolution 1d3k Human serum transferrin 1d4n Human serum transferrin 1dot Crystallographic structure of duck ovotransferrin at 2.3 angstroms resolution 1dsn D60s n-terminal lobe human lactoferrin 1dtg Human transferrin n-lobe mutant h249e 1dtz Structure of camel apo-lactoferrin demonstrates its dual role in sequestering and transporting ferric ions simultaneously:crystal structure of camel apo-lactoferrin at 2.6a resolution. 1eh3 R210k n-terminal lobe human lactoferrin 1f9b Melanin protein interaction: x-ray structure of the complex of mare lactoferrin with melanin monomers 1fck Structure of diceric human lactoferrin 1fqe Crystal structures of mutant (k206a) that abolish the dilysine interaction in the n-lobe of human transferrin 1fqf Crystal structures of mutant (k296a) that abolish the dilysine interaction in the n-lobe of human transferrin 1gv8 Kda fragment of n-ii domain of duck ovotransferrin 1gvc 18kda n-ii domain fragment of duck ovotransferrin + nta 1h43 R210e n-terminal lobe human lactoferrin 1h44 R210l n-terminal lobe human lactoferrin 1h45 R210g n-terminal lobe human lactoferrin 1h76 The crystal structure of diferric porcine serum transferrin 1hse H253m n terminal lobe of human lactoferrin 1i6b Structure of equine apolactoferrin at 3.2 a resolution using crystals grown at 303k 1i6q Formation of a protein intermediate and its trapping by the simultaneous crystallization process: crystal structure of an iron-saturated intermediate in the fe3+ binding pathway of camel lactoferrin at 2.7 resolution 1iej Ovotransferrin, n-terminal lobe, holo form, at 1.65 a resolution 1iq7 Ovotransferrin, c-terminal lobe, apo form 1jnf Rabbit serum transferrin at 2.6 a resolution. 1jqf Human transferrin n-lobe mutant h249q 1jw1 Crystallization and structure determination of goat lactoferrin at 4.0 resolution: a new form of packing in lactoferrins with a high solvent content in crystals 1l5t Crystal structure of a domain-opened mutant (r121d) of the human lactoferrin n-lobe refined from a merohedrally- twinned crystal form. 1lcf Crystal structure of copper-and oxalate-substituted human lactoferrin at 2.0 angstroms resolution 1lct Structure of the recombinant n-terminal lobe of human lactoferrin at 2.0 angstroms resolution 1lfg Molecular replacement solution of the structure of apolactoferrin, a protein displaying large-scale conformational change 1lfh Molecular replacement solution of the structure of apolactoferrin, a protein displaying large-scale conformational change 1lfi Metal substitution in transferrins: the crystal structure of human copper-lactoferrin at 2.1 angstroms resolution 1lgb Interaction of a legume lectin with the n2 fragment of human lactotransferrin or with the isolated biantennary glycopeptide: role of the fucose moiety 1n04 Diferric chicken serum transferrin at 2.8 a resolution. 1n76 Crystal structure of human seminal lactoferrin at 3.4 a resolution 1n7w Crystal structure of human serum transferrin, n-lobe l66w mutant 1n7x Human serum transferrin, n-lobe y45e mutant 1n84 Human serum transferrin, n-lobe 1nft Ovotransferrin, n-terminal lobe, iron loaded open form 1nkx Crystal structure of a proteolytically generated functional monoferric c-lobe of bovine lactoferrin at 1.9a resolution 1nnt Structural evidence for a ph-sensitive di-lysine trigger in the hen ovotransferrin n-lobe: implications for transferrin iron release 1oqg Crystal structure of the d63e mutant of the n-lobe human transferrin 1oqh Crystal structure of the r124a mutant of the n-lobe human transferrin 1ovb The mechanism of iron uptake by transferrins: the structure of an 18kd nii-domain fragment at 2.3 angstroms resolution 1ovt Refined crystallographic structure of hen ovotransferrin at 2.4 angstroms resolution 1qjm Crystal structure of a complex of lactoferrin with a lanthanide ion (sm3+) at 3.4 anstrom resolution 1ryo Human serum transferrin, n-lobe bound with oxalate 1ryx Crystal structure of hen serum transferrin in apo- form 1sdx Crystal structure of the zinc saturated c-terminal half of bovine lactoferrin at 2.0 a resolution reveals two additional zinc binding sites 1sqy Structure of human diferric lactoferrin at 2.5a resolution using crystals grown at ph 6.5 1suv Structure of human transferrin receptor-transferrin complex 1tfa Ovotransferrin, n-terminal lobe, apo form 1tfd High-resolution x-ray studies on rabbit serum transferrin: preliminary structure analysis of the n-terminal half- molecule at 2.3 angstroms resolution 1vfd Human lactoferrin, n-terminal lobe mutant with arg 121 replaced by glu (r121e) 1vfe Human lactoferrin, n-terminal lobe mutant with arg 121 replaced by ser (r121s) 2alu Detection of new binding site in the c-terminal lobe of lactoferrin:crystal structure of the complex formed between bovine lactoferrin and a tetrasaccharide at 2.1a resolution 2ays A conserved non-metallic binding site in the c-terminal lobe of lactoferrin: structure of the complex of c- terminal lobe of bovine lactoferrin with n-acetyl galactosamine at 1.86 a resolution 2b65 Crystal structure of the complex of c-lobe of bovine lactoferrin with maltose at 1.5a resolution 2bjj Structure of recombinant human lactoferrin produced in the milk of transgenic cows 2d3i Crystal structure of aluminum-bound ovotransferrin at 2.15 angstrom resolution 2doj Crystal structure of the complex of c-terminal lobe of bovine lactoferrin with adenosine at 2.4 a resolution 2dp8 Carbohydrate recognition by lactoferrin: crystal structure of the complex of c-terminal lobe of bovine lactoferrin with trisaccharide at 2.5 a resolution 2dqv Structure of the c-terminal lobe of bovine lactoferrin in complex with galactose at 2.7 a resolution 2ds9 Structure of the complex of c-terminal lobe of bovine lactoferrin with mannose at 2.8 a resolution 2dsf Structure of the complex of c-terminal lobe of bovine lactoferrin with xylose at 2.8a resolution 2dvc Structure of the bovine lactoferrin c-lobe complex with sucrose at 3.0 a resolution 2dwa Structure of the complex of lactoferrin c-terminal half with fucose at 2.07 a resolution 2dwh Crystal structure of n-acetylglucosamine complex of bovine lactoferrin c-lobe at 2.8 a resolution 2dwi Crystal structure of the complex formed between c-terminal half of bovine lactoferrin and cellobiose at 2.2 a resolution 2dwj Structure of the complex of c-terminal lobe of bovine lactoferrin with raffinose at 2.3 a resolution 2dxr Crystal structure of the complex formed between c-terminal half of bovine lactoferrin and sorbitol at 2.85 a resolution 2dxy Structure of the complex of c-terminal lobe of bovine lactoferrin with trehalose at 2.0 a resolution 2dyx Structure of the complex of lactoferrin c-lobe with melibiose at 2.0 a resolution 2e0s Carbohydrate recognition of c-terminal half of lactoferrin: crystal structure of the complex of c-lobe with rhamnose at 2.15 a resolution 2e1s Crystal structure of the complex of c-terminal half of bovine lactoferrin and arabinose at 2.7 a resolution 2fa7 Crystal structure of the complex of bovine lactoferrin c- lobe with a pentasaccharide at 2.38 a resolution 2g93 Ligand recognition site in c-lobe of lactoferrin: crystal structure of the complex of c-lobe of bovine lactoferrin with methyl alpha-d-mannopyranoside at 1.9 a resolution 2h4i Crystal structure of the complex of proteolytically produced c-terminal half of bovine lactoferrin with lactose at 2.55 a resolution 2hau Apo-human serum transferrin (non-glycosylated) 2hav Apo-human serum transferrin (glycosylated) 2hca Crystal structure of bovine lactoferrin c-lobe liganded with glucose at 2.8 a resolution 2nuv Crystal structure of the complex of c-terminal lobe of bovine lactoferrin with atenolol at 2.25 a resolution 2nwj Structure of the complex of c-terminal lobe of bovine lactoferrin with disaccharide at 1.75 a resolution 2o1l Structure of a complex of c-terminal lobe of bovine lactoferrin with disaccharide at 1.97 a resolution 2o51 Crystal structure of bovine c-lobe with fructose at 3.0 a resolution 2o7u Crystal structure of k206e/k296e mutant of the n-terminal half molecule of human transferrin 2o84 Crystal structure of k206e mutant of n-lobe human transferrin 2ocu Structure of the complex of c-terminal lobe of bovine lactoferrin with n-(4-hydroxyphenyl) acetamide at 2.38 a resolution 2p1s Crystal structure of the c-terminal lobe of bovine lactoferrin complexed with o-alpha-d-glucopyranosyl-(1 3)- alpha-d-fructofuranosyl- (2 1)- alpha-d-glucopyranoside at 1.93 a resolution 2pms Crystal structure of the complex of human lactoferrin n- lobe and lactoferrin-binding domain of pneumococcal surface protein a 2px1 Crystal structure of the complex of bovine lactoferrin c- lobe with ribose at 2.5 a resolution 2q8j Crystal structure of the complex of c-lobe of bovine lactoferrin with mannitol and mannose at 2.7 a resolution 2qje Crystal structure of the complex of bovine c-lobe with amygdalin at 2.3a resolution 2r71 Crystal structure of the complex of bovine c-lobe with inositol at 2.1a resolution 2r9j Ligand recognition in c-lobe: the crystal structure of the complex of lactoferrin c-lobe with nicotinamide at 2.5 a resolution 2zmb Crystal structure of the complex of c-terminal lobe of bovine lactoferrin with parecoxib at 2.9 a resolution 3cfl Crystal structure of the complex formed between c-lobe of bovine lactoferrin and 5-chloro-6'-methyl-3-[4- (methylsulfonyl)phenyl]-2,3'-bipyridine at 2.25 a resolution 3ci8 Crystal structure of the complex of c-lobe of lactoferrin with vitamin b3 (niacin) at 2.4 a resolution 3cr9 Crystal structure of the complex of lactoferrin with 6- (hydroxymethyl)oxane-2,3,4,5-tetrol at 3.49 a resolution 3crb Crystal structure of the complex of c-lobe of lactoferrin with 2-chromenone at 2.6 a resolution 3e9x Crystal structure of the complex of c-lobe of lactoferrin with nimesulide at 2.7 a resolution 3fgs Crystal structure of g65r/k206e double mutant of the n-lobe human transferrin 3iaz Structural basis of the prevention of nsaid-induced damage of the gastrointestinal tract by c-terminal half (c-lobe) of bovine colostrum protein lactoferrin: binding and structural studies of the c-lobe complex with aspirin 3ib0 Structural basis of the prevention of nsaid-induced damage of the gastrointestinal tract by c-terminal half (c-lobe) of bovine colostrum protein lactoferrin: binding and structural studies of c-lobe complex with diclofenac 3ib1 Structural basis of the prevention of nsaid-induced damage of the gastrointestinal tract by c-terminal half (c-lobe) of bovine colostrum protein lactoferrin: binding and structural studies of c-lobe complex with indomethacin 3ib2 Structure of the complex of c-terminal half (c-lobe) of bovine lactoferrin with alpha-methyl-4-(2-methylpropyl) benzene acetic acid 3k0v Removal of sugars and sugars-like molecules from the solution by c-lobe of lactoferrin: crystal structure of the complex of c-lobe with beta-d-glucopyranosyl-(1->4)-beta-d- galactopyranosyl-(1->4)-alpha-d-glucopyranose at 1.9 a resolution
- Links (links to other resources describing this domain)
INTERPRO IPR001156 PROSITE PS00207