UniProt functional annotation for P02788



	UniProt functional annotation for P02788

UniProt code: P02788.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. {ECO:0000269|PubMed:22900286}.

Function: [Lactotransferrin]: Major iron-binding and multifunctional protein found in exocrine fluids such as breast milk and mucosal secretions (PubMed:14573629, PubMed:1599934, PubMed:6802759, PubMed:3169987, PubMed:11179314, PubMed:12693969). Has antimicrobial activity, which depends on the extracellular cation concentration (PubMed:6802759). Antimicrobial properties include bacteriostasis, which is related to its ability to sequester free iron and thus inhibit microbial growth, as well as direct bactericidal properties leading to the release of lipopolysaccharides from the bacterial outer membrane (PubMed:14573629, PubMed:1599934, PubMed:6802759, PubMed:3169987, PubMed:11179314, PubMed:12693969). Can also prevent bacterial biofilm development in P.aeruginosa infection (PubMed:12037568). Has weak antifungal activity against C.albicans (PubMed:11083624). Has anabolic, differentiating and anti-apoptotic effects on osteoblasts and can also inhibit osteoclastogenesis, possibly playing a role in the regulation of bone growth (PubMed:15166119). Promotes binding of species C adenoviruses to epithelial cells, promoting adenovirus infection (PubMed:17079302). Can inhibit papillomavirus infections (PubMed:17481742). Stimulates the TLR4 signaling pathway leading to NF- kappa-B activation and subsequent pro-inflammatory cytokine production while also interfering with the lipopolysaccharide (LPS)-stimulated TLR4 signaling (PubMed:20345905). Inhibits neutrophil granulocyte migration to sites of apoptosis, when secreted by apoptotic cells (PubMed:19033648). Stimulates VEGFA-mediated endothelial cell migration and proliferation (PubMed:16842782). Binds heparin, chondroitin sulfate and possibly other glycosaminoglycans (GAGs) (PubMed:9359845). Also binds specifically to pneumococcal surface protein A (pspA), the lipid A portion of bacterial lipopolysaccharide (LPS), lysozyme and DNA (PubMed:9359845). {ECO:0000269|PubMed:11083624, ECO:0000269|PubMed:11179314, ECO:0000269|PubMed:12037568, ECO:0000269|PubMed:12693969, ECO:0000269|PubMed:14573629, ECO:0000269|PubMed:15166119, ECO:0000269|PubMed:1599934, ECO:0000269|PubMed:16842782, ECO:0000269|PubMed:17079302, ECO:0000269|PubMed:17481742, ECO:0000269|PubMed:19033648, ECO:0000269|PubMed:20345905, ECO:0000269|PubMed:3169987, ECO:0000269|PubMed:6802759, ECO:0000269|PubMed:9359845}.

Function: Lactoferricin binds to the bacterial surface and is crucial for the bactericidal functions. Has some antiviral activity against papillomavirus infection (PubMed:17481742). N-terminal region shows strong antifungal activity against C.albicans (PubMed:11083624). Contains two BBXB heparin-binding consensus sequences that appear to form the predominate functional GAG-binding site. {ECO:0000269|PubMed:11083624, ECO:0000269|PubMed:17481742}.

Function: [Kaliocin-1]: Has antimicrobial activity and is able to permeabilize different ions through liposomal membranes. {ECO:0000269|PubMed:12693969}.

Function: [Lactoferroxin-A]: Has opioid antagonist activity (PubMed:1369293). Shows preference for mu-receptor (PubMed:1369293). {ECO:0000269|PubMed:1369293}.

Function: [Lactoferroxin-B]: Has opioid antagonist activity (PubMed:1369293). Shows higher degrees of preference for kappa- receptors than for mu-receptors (PubMed:1369293). {ECO:0000269|PubMed:1369293}.

Function: [Lactoferroxin-C]: Has opioid antagonist activity (PubMed:1369293). Shows higher degrees of preference for kappa- receptors than for mu-receptors (PubMed:1369293). {ECO:0000269|PubMed:1369293}.

Function: The lactotransferrin transferrin-like domain 1 functions as a serine protease of the peptidase S60 family that cuts arginine rich regions (PubMed:12535064). This function contributes to the antimicrobial activity (PubMed:12535064). Shows a preferential cleavage at -Arg-Ser-Arg-Arg-|- and -Arg-Arg-Ser-Arg-|-, and of Z-Phe-Arg-|- aminomethylcoumarin sites (PubMed:12535064). {ECO:0000269|PubMed:12535064}.

Function: [Isoform DeltaLf]: transcription factor with antiproliferative properties and ability to induce cell cycle arrest (PubMed:15222485). Binds to the DeltaLf response element found in the SKP1, BAX, DCPS, and SELENOH promoters (PubMed:22320386). {ECO:0000269|PubMed:15222485, ECO:0000269|PubMed:22320386}.

Subunit: Monomer. Found in a complex with LTF, CLU, EPPIN and SEMG1. {ECO:0000269|PubMed:10089347, ECO:0000269|PubMed:10828980, ECO:0000269|PubMed:11128996, ECO:0000269|PubMed:12450380, ECO:0000269|PubMed:15299444, ECO:0000269|PubMed:15299793, ECO:0000269|PubMed:15687491, ECO:0000269|PubMed:1581307, ECO:0000269|PubMed:16201406, ECO:0000269|PubMed:17543335, ECO:0000269|PubMed:17567961, ECO:0000269|PubMed:22900286, ECO:0000269|PubMed:8371268, ECO:0000269|PubMed:8594202, ECO:0000269|PubMed:8703903, ECO:0000269|PubMed:8931543, ECO:0000269|PubMed:9003186, ECO:0000269|Ref.71, ECO:0000269|Ref.74, ECO:0000269|Ref.75}.

Subcellular location: [Isoform 1]: Secreted. Cytoplasmic granule. Note=Secreted into most exocrine fluids by various endothelial cells. Stored in the secondary granules of neutrophils.

Subcellular location: [Isoform DeltaLf]: Cytoplasm. Nucleus. Note=Mainly localized in the cytoplasm.

Tissue specificity: High levels are found in saliva and tears, intermediate levels in serum and plasma, and low levels in urine. In kidney, detected in the distal collecting tubules in the medulla but not in the cortical region or in blood vessels. Detected in peripheral blood neutrophils (at protein level). Isoform 1 and isoform DeltaLf are expressed in breast, prostate, spleen, pancreas, kidney, small intestine, lung, skeletal muscle, uterus, thymus and fetal liver. Isoform 1 is expressed in brain, testis and peripheral blood leukocytes; isoform DeltaLf is barely detectable in these tissues. Isoform DeltaLf is expressed in placenta, liver and ovary; isoform 1 is barely detectable in these tissues. In kidney, isoform 1 is expressed at high levels in the collecting tubules of the medulla but at very low levels in the cortex. {ECO:0000269|PubMed:10792619, ECO:0000269|PubMed:2981589, ECO:0000269|PubMed:9122171}.

Ptm: [Isoform DeltaLf]: Phosphorylation at Ser-10 activates the transcriptional activity (PubMed:20404350). Phosphorylation at Ser-10 also promotes proteasomal degradation (PubMed:20404350). Alternatively can undergo O-GlcNAcylation at Ser-10 (PubMed:20404350). {ECO:0000269|PubMed:20404350}.

Ptm: [Isoform DeltaLf]: O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively regulates the transcriptional activity (PubMed:20404350). Alternatively can undergo phosphorylation at Ser-10 (PubMed:20404350). {ECO:0000269|PubMed:20404350}.

Ptm: Poly-N-acetyllactosaminic carbohydrate moiety seems to be needed for TLR4 activation.

Mass spectrometry: [Lactoferricin-H]: Mass=5737.8; Method=Electrospray; Evidence={ECO:0000269|PubMed:16048952};

Polymorphism: The sequence shown corresponds to the reference genome sequence and is likely to represent the minor allele, whereas most publications refer to the longer sequence containing variant Arg-22 ins. Insertion of the additional arginine in variant Arg-22 ins creates an N-terminal basic cluster of four arginines, all of which appear to be important for the full functionality of the protein, including bactericidal and antifungal activities as well as binding to glycosaminoglycans, pspA, LPS, lysozyme and DNA.

Miscellaneous: [Isoform DeltaLf]: Contains a phosphoserine at position 10 (alternate). Contains a O-linked (GlcNAc) serine at position 10 (alternate). O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively regulates DeltaLf transcriptional activity, whereas phosphorylation activates it. Phosphorylation at Ser-10 also promotes proteasomal degradation. {ECO:0000305}.

Similarity: Belongs to the transferrin family. {ECO:0000255|PROSITE- ProRule:PRU00741}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. {ECO:0000269\|PubMed:22900286}.



Function:		[Lactotransferrin]: Major iron-binding and multifunctional protein found in exocrine fluids such as breast milk and mucosal secretions (PubMed:14573629, PubMed:1599934, PubMed:6802759, PubMed:3169987, PubMed:11179314, PubMed:12693969). Has antimicrobial activity, which depends on the extracellular cation concentration (PubMed:6802759). Antimicrobial properties include bacteriostasis, which is related to its ability to sequester free iron and thus inhibit microbial growth, as well as direct bactericidal properties leading to the release of lipopolysaccharides from the bacterial outer membrane (PubMed:14573629, PubMed:1599934, PubMed:6802759, PubMed:3169987, PubMed:11179314, PubMed:12693969). Can also prevent bacterial biofilm development in P.aeruginosa infection (PubMed:12037568). Has weak antifungal activity against C.albicans (PubMed:11083624). Has anabolic, differentiating and anti-apoptotic effects on osteoblasts and can also inhibit osteoclastogenesis, possibly playing a role in the regulation of bone growth (PubMed:15166119). Promotes binding of species C adenoviruses to epithelial cells, promoting adenovirus infection (PubMed:17079302). Can inhibit papillomavirus infections (PubMed:17481742). Stimulates the TLR4 signaling pathway leading to NF- kappa-B activation and subsequent pro-inflammatory cytokine production while also interfering with the lipopolysaccharide (LPS)-stimulated TLR4 signaling (PubMed:20345905). Inhibits neutrophil granulocyte migration to sites of apoptosis, when secreted by apoptotic cells (PubMed:19033648). Stimulates VEGFA-mediated endothelial cell migration and proliferation (PubMed:16842782). Binds heparin, chondroitin sulfate and possibly other glycosaminoglycans (GAGs) (PubMed:9359845). Also binds specifically to pneumococcal surface protein A (pspA), the lipid A portion of bacterial lipopolysaccharide (LPS), lysozyme and DNA (PubMed:9359845). {ECO:0000269\|PubMed:11083624, ECO:0000269\|PubMed:11179314, ECO:0000269\|PubMed:12037568, ECO:0000269\|PubMed:12693969, ECO:0000269\|PubMed:14573629, ECO:0000269\|PubMed:15166119, ECO:0000269\|PubMed:1599934, ECO:0000269\|PubMed:16842782, ECO:0000269\|PubMed:17079302, ECO:0000269\|PubMed:17481742, ECO:0000269\|PubMed:19033648, ECO:0000269\|PubMed:20345905, ECO:0000269\|PubMed:3169987, ECO:0000269\|PubMed:6802759, ECO:0000269\|PubMed:9359845}.



Function:		Lactoferricin binds to the bacterial surface and is crucial for the bactericidal functions. Has some antiviral activity against papillomavirus infection (PubMed:17481742). N-terminal region shows strong antifungal activity against C.albicans (PubMed:11083624). Contains two BBXB heparin-binding consensus sequences that appear to form the predominate functional GAG-binding site. {ECO:0000269\|PubMed:11083624, ECO:0000269\|PubMed:17481742}.



Function:		[Kaliocin-1]: Has antimicrobial activity and is able to permeabilize different ions through liposomal membranes. {ECO:0000269\|PubMed:12693969}.



Function:		[Lactoferroxin-A]: Has opioid antagonist activity (PubMed:1369293). Shows preference for mu-receptor (PubMed:1369293). {ECO:0000269\|PubMed:1369293}.



Function:		[Lactoferroxin-B]: Has opioid antagonist activity (PubMed:1369293). Shows higher degrees of preference for kappa- receptors than for mu-receptors (PubMed:1369293). {ECO:0000269\|PubMed:1369293}.



Function:		[Lactoferroxin-C]: Has opioid antagonist activity (PubMed:1369293). Shows higher degrees of preference for kappa- receptors than for mu-receptors (PubMed:1369293). {ECO:0000269\|PubMed:1369293}.



Function:		The lactotransferrin transferrin-like domain 1 functions as a serine protease of the peptidase S60 family that cuts arginine rich regions (PubMed:12535064). This function contributes to the antimicrobial activity (PubMed:12535064). Shows a preferential cleavage at -Arg-Ser-Arg-Arg-\|- and -Arg-Arg-Ser-Arg-\|-, and of Z-Phe-Arg-\|- aminomethylcoumarin sites (PubMed:12535064). {ECO:0000269\|PubMed:12535064}.



Function:		[Isoform DeltaLf]: transcription factor with antiproliferative properties and ability to induce cell cycle arrest (PubMed:15222485). Binds to the DeltaLf response element found in the SKP1, BAX, DCPS, and SELENOH promoters (PubMed:22320386). {ECO:0000269\|PubMed:15222485, ECO:0000269\|PubMed:22320386}.


Subunit:		Monomer. Found in a complex with LTF, CLU, EPPIN and SEMG1. {ECO:0000269\|PubMed:10089347, ECO:0000269\|PubMed:10828980, ECO:0000269\|PubMed:11128996, ECO:0000269\|PubMed:12450380, ECO:0000269\|PubMed:15299444, ECO:0000269\|PubMed:15299793, ECO:0000269\|PubMed:15687491, ECO:0000269\|PubMed:1581307, ECO:0000269\|PubMed:16201406, ECO:0000269\|PubMed:17543335, ECO:0000269\|PubMed:17567961, ECO:0000269\|PubMed:22900286, ECO:0000269\|PubMed:8371268, ECO:0000269\|PubMed:8594202, ECO:0000269\|PubMed:8703903, ECO:0000269\|PubMed:8931543, ECO:0000269\|PubMed:9003186, ECO:0000269\|Ref.71, ECO:0000269\|Ref.74, ECO:0000269\|Ref.75}.
Subcellular location:		[Isoform 1]: Secreted. Cytoplasmic granule. Note=Secreted into most exocrine fluids by various endothelial cells. Stored in the secondary granules of neutrophils.
Subcellular location:		[Isoform DeltaLf]: Cytoplasm. Nucleus. Note=Mainly localized in the cytoplasm.
Tissue specificity:		High levels are found in saliva and tears, intermediate levels in serum and plasma, and low levels in urine. In kidney, detected in the distal collecting tubules in the medulla but not in the cortical region or in blood vessels. Detected in peripheral blood neutrophils (at protein level). Isoform 1 and isoform DeltaLf are expressed in breast, prostate, spleen, pancreas, kidney, small intestine, lung, skeletal muscle, uterus, thymus and fetal liver. Isoform 1 is expressed in brain, testis and peripheral blood leukocytes; isoform DeltaLf is barely detectable in these tissues. Isoform DeltaLf is expressed in placenta, liver and ovary; isoform 1 is barely detectable in these tissues. In kidney, isoform 1 is expressed at high levels in the collecting tubules of the medulla but at very low levels in the cortex. {ECO:0000269\|PubMed:10792619, ECO:0000269\|PubMed:2981589, ECO:0000269\|PubMed:9122171}.
Ptm:		[Isoform DeltaLf]: Phosphorylation at Ser-10 activates the transcriptional activity (PubMed:20404350). Phosphorylation at Ser-10 also promotes proteasomal degradation (PubMed:20404350). Alternatively can undergo O-GlcNAcylation at Ser-10 (PubMed:20404350). {ECO:0000269\|PubMed:20404350}.
Ptm:		[Isoform DeltaLf]: O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively regulates the transcriptional activity (PubMed:20404350). Alternatively can undergo phosphorylation at Ser-10 (PubMed:20404350). {ECO:0000269\|PubMed:20404350}.
Ptm:		Poly-N-acetyllactosaminic carbohydrate moiety seems to be needed for TLR4 activation.
Mass spectrometry:		[Lactoferricin-H]: Mass=5737.8; Method=Electrospray; Evidence={ECO:0000269\|PubMed:16048952};
Polymorphism:		The sequence shown corresponds to the reference genome sequence and is likely to represent the minor allele, whereas most publications refer to the longer sequence containing variant Arg-22 ins. Insertion of the additional arginine in variant Arg-22 ins creates an N-terminal basic cluster of four arginines, all of which appear to be important for the full functionality of the protein, including bactericidal and antifungal activities as well as binding to glycosaminoglycans, pspA, LPS, lysozyme and DNA.
Miscellaneous:		[Isoform DeltaLf]: Contains a phosphoserine at position 10 (alternate). Contains a O-linked (GlcNAc) serine at position 10 (alternate). O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively regulates DeltaLf transcriptional activity, whereas phosphorylation activates it. Phosphorylation at Ser-10 also promotes proteasomal degradation. {ECO:0000305}.
Similarity:		Belongs to the transferrin family. {ECO:0000255\|PROSITE- ProRule:PRU00741}.