P02760 · AMBP_HUMAN

  • Protein
    Protein AMBP
  • Gene
    AMBP
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Alpha-1-microglobulin

Antioxidant and tissue repair protein with reductase, heme-binding and radical-scavenging activities. Removes and protects against harmful oxidants and repairs macromolecules in intravascular and extravascular spaces and in intracellular compartments (PubMed:11877257, PubMed:15683711, PubMed:22096585, PubMed:23157686, PubMed:23642167, PubMed:25698971, PubMed:32092412, PubMed:32823731).
Intravascularly, plays a regulatory role in red cell homeostasis by preventing heme- and reactive oxygen species-induced cell damage. Binds and degrades free heme to protect fetal and adult red blood cells from hemolysis (PubMed:11877257, PubMed:32092412).
Reduces extracellular methemoglobin, a Fe3+ (ferric) form of hemoglobin that cannot bind oxygen, back to the Fe2+ (ferrous) form deoxyhemoglobin, which has oxygen-carrying potential (PubMed:15683711).
Upon acute inflammation, inhibits oxidation of low-density lipoprotein particles by MPO and limits vascular damage (PubMed:25698971).
Extravascularly, protects from oxidation products formed on extracellular matrix structures and cell membranes. Catalyzes the reduction of carbonyl groups on oxidized collagen fibers and preserves cellular and extracellular matrix ultrastructures (PubMed:22096585, PubMed:23642167).
Importantly, counteracts the oxidative damage at blood-placenta interface, preventing leakage of free fetal hemoglobin into the maternal circulation (PubMed:21356557).
Intracellularly, has a role in maintaining mitochondrial redox homeostasis. Bound to complex I of the respiratory chain of mitochondria, may scavenge free radicals and preserve mitochondrial ATP synthesis. Protects renal tubule epithelial cells from heme-induced oxidative damage to mitochondria (PubMed:23157686, PubMed:32823731).
Reduces cytochrome c from Fe3+ (ferric) to the Fe2+ (ferrous) state through formation of superoxide anion radicals in the presence of ascorbate or NADH/NADPH electron donor cofactors, ascorbate being the preferred cofactor (PubMed:15683711).
Has a chaperone role in facilitating the correct folding of bikunin in the endoplasmic reticulum compartment (By similarity).

Inter-alpha-trypsin inhibitor light chain

Kunitz-type serine protease inhibitor and structural component of extracellular matrix with a role in extracellular space remodeling and cell adhesion (PubMed:20463016, PubMed:25301953).
Among others, has antiprotease activity toward kallikrein, a protease involved in airway inflammation; inhibits GZMK/granzyme, a granule-stored serine protease involved in NK and T cell cytotoxic responses; and inhibits PLG/plasmin, a protease required for activation of matrix metalloproteinases (PubMed:10480954, PubMed:15917224, PubMed:16873769).
As part of I-alpha-I complex, provides for the heavy chains to be transferred from I-alpha-I complex to hyaluronan in the presence of TNFAIP6, in a dynamic process that releases free bikunin and remodels extracellular matrix proteoglycan structures. Free bikunin, but not its heavy chain-bound form, acts as potent protease inhibitor in airway secretions (PubMed:16873769).
Part of hyaluronan-rich extracellular matrix that surrounds oocyte during cumulus oophorus expansion, an indispensable process for proper ovulation (By similarity).
Also inhibits calcium oxalate crystallization (PubMed:7676539).

Trypstatin

Kunitz-type serine protease inhibitor. Has high catalytic efficiency for F10/blood coagulation factor Xa and may act as an anticoagulant by inhibiting prothrombin activation. Inhibits trypsin and mast cell CMA1/chymase and tryptase proteases.

Miscellaneous

In vitro, the first twelve residues of the amino end of the inhibitor appear to have a reactive site capable of inhibiting the activity of a number of enzymes. Its in vivo function is not known.

Activity regulation

Inter-alpha-trypsin inhibitor light chain

Up-regulated by TNFAIP6. In a transesterification reaction, TNFAIP6 cleaves the ester bond between the heavy chain and the chondroitin sulfate chain in I-alpha-I complex and potentiates the antiprotease function of I-alpha-I complex through release of free bikunin.

pH Dependence

The reductase activity toward cytochrome c increases at alkaline pH 8-9 when compared to pH 6-7.

Features

Showing features for binding site, site.

TypeIDPosition(s)Description
Binding site533-hydroxy-L-kynurenine (UniProtKB | ChEBI); multimeric 3-hydroxykynurenine chromophore; covalent
Binding site1113-hydroxy-L-kynurenine (UniProtKB | ChEBI); multimeric 3-hydroxykynurenine chromophore; covalent
Binding site1373-hydroxy-L-kynurenine (UniProtKB | ChEBI); multimeric 3-hydroxykynurenine chromophore; covalent
Binding site1493-hydroxy-L-kynurenine (UniProtKB | ChEBI); multimeric 3-hydroxykynurenine chromophore; covalent
Site199Cleavage; in the presence of oxyhemoglobin or MPO
Site241-242Inhibitory (P1) (chymotrypsin, elastase)
Site297-298Inhibitory (P1) (trypsin)

GO annotations

AspectTerm
Cellular Componentblood microparticle
Cellular Componentcell surface
Cellular Componentcollagen-containing extracellular matrix
Cellular Componentcytosol
Cellular Componentendoplasmic reticulum
Cellular Componentextracellular exosome
Cellular Componentextracellular region
Cellular Componentextracellular space
Cellular Componentmitochondrial inner membrane
Cellular Componentnuclear membrane
Cellular Componentplasma membrane
Molecular Functioncalcium channel inhibitor activity
Molecular Functioncalcium oxalate binding
Molecular Functioncarbohydrate binding
Molecular Functionheme binding
Molecular FunctionIgA binding
Molecular Functionoxidoreductase activity
Molecular Functionprotein homodimerization activity
Molecular Functionserine-type endopeptidase inhibitor activity
Biological Processcell adhesion
Biological Processfemale pregnancy
Biological Processheme catabolic process
Biological Processnegative regulation of immune response
Biological Processnegative regulation of JNK cascade

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

Gene names

    • Name
      AMBP
    • Synonyms
      HCP, ITIL

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo

Accessions

  • Primary accession
    P02760
  • Secondary accessions
    • P00977
    • P02759
    • P78491
    • Q2TU33
    • Q5TBD7

Proteomes

Organism-specific databases

Subcellular Location

Alpha-1-microglobulin

Secreted
Endoplasmic reticulum
Cytoplasm, cytosol
Cell membrane
; Peripheral membrane protein
Nucleus membrane
; Peripheral membrane protein
Mitochondrion inner membrane
; Peripheral membrane protein
Note: The cellular uptake occurs via a non-endocytotic pathway and allows for localization to various membrane structures. A specific binding to plasma membrane suggests the presence of a cell receptor, yet to be identified. Directly binds collagen fibers type I.

Inter-alpha-trypsin inhibitor light chain

Secreted

Keywords

Disease & Variants

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis53Impairs the reductase activity toward cytochrome c independently of the electron donnor. Decreases the reductase activity toward methemoglobin. Decreases the reductase activity toward oxidized collagen.
Mutagenesis111Impairs the reductase activity toward cytochrome c in the presence of NADPH; when associated with T-137 and T-149. Impairs the reductase activity toward oxidized collagen; when associated with T-137 and T-149.
Mutagenesis137Impairs the reductase activity toward cytochrome c in the presence of NADPH; when associated with T-111 and T-149. Impairs the reductase activity toward oxidized collagen; when associated with T-111 and T-149.
Mutagenesis149Impairs the reductase activity toward cytochrome c in the presence of NADPH; when associated with T-111 and T-137. Impairs the reductase activity toward oxidized collagen; when associated with T-111 and T-137.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 443 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Organism-specific databases

Miscellaneous

Genetic variation databases

PTM/Processing

Features

Showing features for signal, chain, glycosylation, disulfide bond.

TypeIDPosition(s)Description
Signal1-19
ChainPRO_000001788620-203Alpha-1-microglobulin
GlycosylationCAR_00017224O-linked (GalNAc...) threonine
Glycosylation36N-linked (GlcNAc...) (complex) asparagine
Disulfide bond91↔188
Glycosylation115N-linked (GlcNAc...) (complex) asparagine
ChainPRO_0000017887206-352Inter-alpha-trypsin inhibitor light chain
Glycosylation215O-linked (Xyl...) (chondroitin sulfate) serine
Disulfide bond231↔281
Disulfide bond240↔264
Glycosylation250N-linked (GlcNAc...) (complex) asparagine
Disulfide bond256↔277
ChainPRO_0000318926284-344Trypstatin
Disulfide bond287↔337
Disulfide bond296↔320
Disulfide bond312↔333

Post-translational modification

The precursor is proteolytically processed into separately functioning proteins.

Alpha-1-microglobulin

Proteolytically cleaved in the presence of oxyhemoglobin or MPO (PubMed:11877257, PubMed:25698971).
The cleaved form t-alpha-1-microglobulin lacks the C-terminal tetrapeptide LIPR and is released from IgA-alpha-1-microglobulin complex as well as from free alpha-1-microglobulin when exposed to oxyhemoglobin or erythrocyte membranes. The cleavage of IgA-alpha-1-microglobulin complex is associated with the reduction of the covalent bond between IgA and alpha-1-microglobulin, yielding an intact IgA molecule (PubMed:11877257).
The cleavage by MPO is associated with the transfer of heme group from MPO to t-alpha-1-microglobulin (PubMed:25698971).
t-alpha-1-microglobulin has higher reductase activity when compared with full length protein (PubMed:15683711).

Alpha-1-microglobulin

3-hydroxykynurenine, an oxidized tryptophan metabolite that is common in biological fluids, reacts with Cys-53, Lys-111, Lys-137, and Lys-149 to form heterogeneous polycyclic chromophores including hydroxanthommatin. The reaction by alpha-1-microglobulin is autocatalytic; the human protein forms chromophore even when expressed in insect and bacterial cells. The chromophore can react with accessible cysteines forming non-reducible thioether cross-links with other molecules of alpha-1-microglobulin or with other proteins such as Ig alpha-1 chain C region 'Cys-352'.

Inter-alpha-trypsin inhibitor light chain

Heavy chains are interlinked with bikunin via a chondroitin 4-sulfate bridge to the C-terminal aspartate.

Inter-alpha-trypsin inhibitor light chain

Proteolytically cleaved by PRSS3 at Kunitz domain 2.
N-glycosylated. N-glycan heterogeneity at Asn-115: Hex5HexNAc4 (major), Hex6HexNAc5 (minor) and dHex1Hex6HexNAc5 (minor). N-glycan at Asn-250: Hex5HexNAc4.
O-glycosylated. O-linkage of the glycosaminoglycan, chondroitin sulfate, at Ser-215 allows cross-linking between the three polypeptide chains.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Alpha-1-microglobulin

Expressed by the liver and secreted in plasma. Occurs in many physiological fluids including plasma, urine, and cerebrospinal fluid (PubMed:11877257).
Expressed in epidermal keratinocytes, in dermis and epidermal-dermal junction (at protein level) (PubMed:22096585).
Expressed in red blood cells (at protein level) (PubMed:32092412).
Expressed in placenta (PubMed:21356557).

Inter-alpha-trypsin inhibitor light chain

Detected in placenta (at protein level) (PubMed:32337544).
Detected in cerebrospinal fluid, plasma and urine (at protein level) (PubMed:25326458, PubMed:36213313, PubMed:37453717).
Expressed in airway epithelium and submucosal gland (at protein level). Colocalizes with TNFAIP6 at the ciliary border. Present in bronchoalveolar lavage fluid (at protein level)

Induction

Alpha-1-microglobulin

Up-regulated upon oxidative stress (PubMed:21356557, PubMed:22096585, PubMed:23642167).
Up-regulated in keratinocytes upon exposure to heme and reactive oxygen species (PubMed:22096585).
Up-regulated in hemoglobin-perfused placenta (PubMed:21356557).

Inter-alpha-trypsin inhibitor light chain

Up-regulated in airway epithelium and submucosal gland in response to inflammatory cytokine TNF.

Gene expression databases

Organism-specific databases

Interaction

Subunit

Alpha-1-microglobulin

Monomer (PubMed:22512701, PubMed:9183005).
Homodimer (PubMed:9183005).
In plasma, it occurs as a monomer or dimer and in covalently-linked complexes with immunoglobulin A (IgA), ALB/albumin and F2/prothrombin (PubMed:9183005).
Chromophore-bound alpha-1-microglobulin interacts with the constant region of immunoglobulin A (PubMed:9183005).
Chromophore-bound alpha-1-microglobulin interacts with ALB with molar ratio 2:1 and 1:1; this interaction does not prevent fatty acid binding to ALB (PubMed:9183005).
Interacts with F2/prothrombin (via N-terminus) with molar ratio 2:1 and 1:1; this interaction does not prevent the activation of prothrombin to thrombin (PubMed:9183005).
Interacts with NDUFAB1, a subunit of mitochondrial complex I (PubMed:23157686).
Interacts with FN1 (By similarity).

Inter-alpha-trypsin inhibitor light chain

I-alpha-I plasma protease inhibitors are assembled from one or two heavy chains (HC) and one light chain, bikunin. Inter-alpha-inhibitor (I-alpha-I) is composed of ITIH1/HC1, ITIH2/HC2 and bikunin, and pre-alpha-inhibitor (P-alpha-I) of ITIH3/HC3 and bikunin (PubMed:16873769, PubMed:2476436).
Interacts with TNFAIP6 (via Link domain) (PubMed:15917224).

Trypstatin

Monomer. Also occurs as a complex with tryptase in mast cells.

Alpha-1-microglobulin

(Microbial infection) Interacts with hepatitis E virus/HEV protein ORF3.

Inter-alpha-trypsin inhibitor light chain

(Microbial infection) Interacts with hepatitis E virus/HEV protein ORF3.

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY P02760CTSB P078584EBI-2115136, EBI-715062
BINARY P02760FHL3 Q136433EBI-2115136, EBI-741101

Protein-protein interaction databases

Miscellaneous

Family & Domains

Features

Showing features for region, domain.

TypeIDPosition(s)Description
Region206-226Glycopeptide (secretory piece)
Domain231-281BPTI/Kunitz inhibitor 1
Domain287-337BPTI/Kunitz inhibitor 2

Domain

Inter-alpha-trypsin inhibitor light chain

The Kunitz domains 1 and 2 serve as protease inhibitor domains.

Sequence similarities

In the N-terminal section; belongs to the calycin superfamily. Lipocalin family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    352
  • Mass (Da)
    38,999
  • Last updated
    1987-08-13 v1
  • Checksum
    BC001780094CBD06
MRSLGALLLLLSACLAVSAGPVPTPPDNIQVQENFNISRIYGKWYNLAIGSTCPWLKKIMDRMTVSTLVLGEGATEAEISMTSTRWRKGVCEETSGAYEKTDTDGKFLYHKSKWNITMESYVVHTNYDEYAIFLTKKFSRHHGPTITAKLYGRAPQLRETLLQDFRVVAQGVGIPEDSIFTMADRGECVPGEQEPEPILIPRVRRAVLPQEEEGSGGGQLVTEVTKKEDSCQLGYSAGPCMGMTSRYFYNGTSMACETFQYGGCMGNGNNFVTEKECLQTCRTVAACNLPIVRGPCRAFIQLWAFDAVKGKCVLFPYGGCQGNGNKFYSEKECREYCGVPGDGDEELLRFSN

Computationally mapped potential isoform sequences

There are 2 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
S4R3Y4S4R3Y4_HUMANAMBP238
S4R471S4R471_HUMANAMBP193

Features

Showing features for sequence conflict.

TypeIDPosition(s)Description
Sequence conflict48-57in Ref. 11; AA sequence
Sequence conflict57in Ref. 10; AA sequence and 12; AA sequence
Sequence conflict137in Ref. 11; AA sequence
Sequence conflict142in Ref. 11; AA sequence
Sequence conflict145in Ref. 11; AA sequence
Sequence conflict194in Ref. 11; AA sequence
Sequence conflict215in Ref. 18; AA sequence
Sequence conflict218in Ref. 18; AA sequence
Sequence conflict291-292in Ref. 14; AA sequence and 15; AA sequence
Sequence conflict295in Ref. 15; AA sequence
Sequence conflict343in Ref. 14; AA sequence

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
X04225
EMBL· GenBank· DDBJ
CAA27803.1
EMBL· GenBank· DDBJ
mRNA
X04494
EMBL· GenBank· DDBJ
CAA28182.1
EMBL· GenBank· DDBJ
mRNA
X54816
EMBL· GenBank· DDBJ
CAA38585.1
EMBL· GenBank· DDBJ
Genomic DNA
X54817
EMBL· GenBank· DDBJ
CAA38585.1
EMBL· GenBank· DDBJ
Genomic DNA
X54818
EMBL· GenBank· DDBJ
CAA38585.1
EMBL· GenBank· DDBJ
Genomic DNA
X54817
EMBL· GenBank· DDBJ
CAA38586.1
EMBL· GenBank· DDBJ
Genomic DNA
X54818
EMBL· GenBank· DDBJ
CAA38587.1
EMBL· GenBank· DDBJ
Genomic DNA
M88249
EMBL· GenBank· DDBJ
AAA59196.1
EMBL· GenBank· DDBJ
Genomic DNA
M88165
EMBL· GenBank· DDBJ
AAA59196.1
EMBL· GenBank· DDBJ
Genomic DNA
M88243
EMBL· GenBank· DDBJ
AAA59196.1
EMBL· GenBank· DDBJ
Genomic DNA
M88244
EMBL· GenBank· DDBJ
AAA59196.1
EMBL· GenBank· DDBJ
Genomic DNA
M88246
EMBL· GenBank· DDBJ
AAA59196.1
EMBL· GenBank· DDBJ
Genomic DNA
M88247
EMBL· GenBank· DDBJ
AAA59196.1
EMBL· GenBank· DDBJ
Genomic DNA
AY544123
EMBL· GenBank· DDBJ
AAT11154.1
EMBL· GenBank· DDBJ
mRNA
AK290837
EMBL· GenBank· DDBJ
BAF83526.1
EMBL· GenBank· DDBJ
mRNA
AL137850
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
CH471090
EMBL· GenBank· DDBJ
EAW87404.1
EMBL· GenBank· DDBJ
Genomic DNA
BC041593
EMBL· GenBank· DDBJ
AAH41593.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.
FeedbackHelp