AMBP

Summary

AMBP (alpha-1-microglobulin/bikunin precursor, HGNC:453) is a protein-coding gene on chromosome 9q32, encoding Protein AMBP (P02760). Antioxidant and tissue repair protein with reductase, heme-binding and radical-scavenging activities.

This gene encodes a complex glycoprotein secreted in plasma. The precursor is proteolytically processed into distinct functioning proteins: alpha-1-microglobulin, which belongs to the superfamily of lipocalin transport proteins and may play a role in the regulation of inflammatory processes, and bikunin, which is a urinary trypsin inhibitor belonging to the superfamily of Kunitz-type protease inhibitors and plays an important role in many physiological and pathological processes. This gene is located on chromosome 9 in a cluster of lipocalin genes.

Source: NCBI Gene 259 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 85 total
• MANE Select transcript: NM_001633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:453
Approved symbol	AMBP
Name	alpha-1-microglobulin/bikunin precursor
Location	9q32
Locus type	gene with protein product
Status	Approved
Aliases	UTI, HCP, EDC1, HI30, IATIL, ITILC
Ensembl gene	ENSG00000106927
Ensembl biotype	protein_coding
OMIM	176870
Entrez	259

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 28 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000265132, ENST00000466610, ENST00000540645, ENST00000603230, ENST00000866742, ENST00000866746, ENST00000866748, ENST00000866750, ENST00000866751, ENST00000866752, ENST00000866753, ENST00000866754, ENST00000866755, ENST00000866756, ENST00000866757, ENST00000866758, ENST00000866759, ENST00000866760, ENST00000866761, ENST00000866762, ENST00000866763, ENST00000866764, ENST00000866765, ENST00000866766, ENST00000866767, ENST00000866768, ENST00000866769, ENST00000866770, ENST00000866771, ENST00000866772

RefSeq mRNA: 1 — MANE Select: NM_001633 NM_001633

CCDS: CCDS6800

Canonical transcript exons

ENST00000265132 — 10 exons

Exon	Start	End
ENSE00000926885	114078093	114078300
ENSE00000983923	114061424	114061591
ENSE00000983924	114060925	114061098
ENSE00001034290	114060127	114060270
ENSE00003501522	114074036	114074152
ENSE00003501578	114069699	114069745
ENSE00003551854	114076598	114076740
ENSE00003582983	114062677	114062758
ENSE00003635925	114072925	114073026
ENSE00003686396	114074960	114075036

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 99.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 30.0746 / max 11758.5878, expressed in 149 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102124	27.4657	96
102126	1.3059	65
102125	0.9682	37
102127	0.2007	23
102123	0.0677	8
102120	0.0464	12
102128	0.0146	9
102118	0.0054	5

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.91	gold quality
liver	UBERON:0002107	99.88	gold quality
gall bladder	UBERON:0002110	98.41	gold quality
body of pancreas	UBERON:0001150	96.74	gold quality
pancreas	UBERON:0001264	94.23	gold quality
islet of Langerhans	UBERON:0000006	92.27	gold quality
pancreatic ductal cell	CL:0002079	84.38	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.53	gold quality
oocyte	CL:0000023	81.49	silver quality
epithelial cell of pancreas	CL:0000083	80.67	gold quality
secondary oocyte	CL:0000655	77.00	gold quality
metanephros cortex	UBERON:0010533	76.29	gold quality
adult mammalian kidney	UBERON:0000082	72.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.73	gold quality
nephron tubule	UBERON:0001231	69.25	silver quality
endometrium epithelium	UBERON:0004811	69.19	gold quality
Brodmann (1909) area 10	UBERON:0013541	68.47	gold quality
kidney	UBERON:0002113	67.51	gold quality
adrenal tissue	UBERON:0018303	67.49	gold quality
body of stomach	UBERON:0001161	67.46	gold quality
metanephric glomerulus	UBERON:0004736	67.36	silver quality
metanephros	UBERON:0000081	67.11	gold quality
renal glomerulus	UBERON:0000074	66.95	silver quality
colonic epithelium	UBERON:0000397	65.92	silver quality
stomach	UBERON:0000945	65.85	gold quality
cortex of kidney	UBERON:0001225	65.60	gold quality
frontal pole	UBERON:0002795	65.43	gold quality
kidney epithelium	UBERON:0004819	64.74	silver quality
fundus of stomach	UBERON:0001160	63.79	gold quality
duodenum	UBERON:0002114	63.63	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	14696.69
E-MTAB-10553	yes	10098.29
E-MTAB-7407	yes	7475.69
E-MTAB-6701	yes	6316.58
E-HCAD-9	yes	5423.34
E-MTAB-8495	yes	3780.61
E-ANND-5	yes	771.74
E-GEOD-81547	yes	22.80
E-GEOD-83139	yes	11.17
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXM1, HNF4A

miRNA regulators (miRDB)

2 targeting AMBP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-4433A-3P	97.75	62.82	1435

Literature-anchored findings (GeneRIF, showing 40)

• Transfection into H460M Human large cell lung carcinoma line decreased tumor growth and metastasis in nude mice (PMID:11807786)
• Processing of the lipocalin alpha(1)-microglobulin by hemoglobin induces heme-binding and heme-degradation properties. (PMID:11877257)
• bikunin has a role in downregulating PI3 kinase and suppressing tumor invasiveness and metastasis in ovaran cancer cells (PMID:14597629)
• Data show that alpha(1) -microglobulin/bikunin precursor specifically interacts with the ORF3 protein of hepatitis E virus and has a direct role in enhancing alpha(1)microglobulin export from the hepatocyte. (PMID:15037615)
• alpha-1-microglobulin is covalently bound to kynurenine-derived chromophores (PMID:15452109)
• Bikunin neither decreased expression of TGF-beta receptors (TbetaRI and TbetaRII) in cancer cells nor altered the specific binding of 125I TGF-beta1 to the cells. (PMID:15498571)
• The TSG-6 and inter-alpha-inhibitor interaction promotes a transesterification cleaving the protein-glycosaminoglycan-protein (PGP) cross-link. (PMID:15653696)
• the second processed protein from AMBP, bikunin, strongly interacted with the full-length hepatitis E virus ORF3 protein (PMID:16140784)
• the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (alpha1 microglobulin) from cultured hepatocytes (PMID:16407257)
• The urinary excretion of alpha1-microglobulin and albumin was significantly elevated in nine patients, and the urinary excretion of the two proteins correlated significantly. (PMID:16916777)
• Identification of the protein bikunin as an endogenous, competitive inhibitor of a dynorphin-converting enzyme in human cerebrospinal fluid. (PMID:17087727)
• Free uristatin and bikunin pass readily into urine and are primarily bound to heavy chains that constitute the proinhibitor form in plasma. (PMID:17115277)
• Bikunin was found to localize on the cell membrane, while tryptase was in the secretary granules of the mast cells from psoriatic lesions. (PMID:17146627)
• alpha(1)-microglobulin participates in the defense against oxidation by hemoglobin, heme, and reactive oxygen species (PMID:17320766)
• small angle X-ray scanning study of the monomer and dimer forms of alpha1-microglobulin; monomer is characterised by a radius of gyration R(G)= 2.20 nm and D(max)=6.3 nm and the dimer by R(G)=2.99 nm and D(max)=9.5 nm (PMID:17584166)
• The ability of alpha-1-microglobulin to restore the initial conformation characteristic for the native protein and the internal dynamics after the unfolding of the globule by 10 M urea and 6 M guanidine hydrochloride has been ascertained. (PMID:17633530)
• AMBP has radical scavenging activity. (PMID:17766242)
• urinary trypsin inhibitor is insufficiently produced for neutrophil elastase release after cardiac arrest (PMID:17998887)
• in multiple myeloma patients without renal failure, elevated Alpha-1-microglobulin excretion might be an early marker of renal tubular involvement (PMID:18046670)
• In the present study, structural motifs regulating bikunin’s anti-inflammatory function are delineated. Binding of bikunin to neutrophils is critically important for its anti-inflammatory capacity. (PMID:18226914)
• The transfer of heavy chains from bikunin proteins to hyaluronan requires both TSG-6 and HC2. (PMID:18448433)
• Overexpression of bikunin reduced the gene expression of matriptase, which attenuated in vitro cell invasion in prostate cancer. (PMID:18649735)
• Overexpression of Urinary trypsin inhibitor is associated with recurrence in hepatocellular carcinoma. (PMID:19636634)
• increased protein levels in preeclamptic women (PMID:19879940)
• significant relationship was established between the low level and absence of bikunin, and pro-u-PA in urine samples from patients with bladder tumors; identified bikunin loss in urine as a potential bladder carcinoma marker (PMID:19914646)
• The promoter of AMBP gene had polymorphisms at positions -218 and -189 nt giving three different genotypes with no association between these observed genotypes and kidney stone-forming phenotypes. (PMID:20602574)
• These findings suggest that there was no significant association in genotype distribution of Init-2 polymorphism of the AMBP gene between patients with kidney stones and healthy controls. (PMID:20602574)
• the cell-protective effects of alpha(1)-microglobulin during alpha-particle irradiation (PMID:20954860)
• urinary marker for the differential diagnosis of Balkan endemic nephropathy (PMID:21332340)
• The results suggest that A1M may have a physiological role in protection of skin cells and matrix against oxidative damage following bleeding. (PMID:22096585)
• Report prognostic value of urinary alpha 1-macroglobulin in idiopathic membranous nephropathy. (PMID:22595828)
• crystal of alpha1-microglobulin belonged to space group P4(3), with unit-cell parameters a = b = 36.45, c = 112.68 A (PMID:22684072)
• High urine alpha-1-microglobulin is associated with ischemic acute tubular necrosis than other causes of acute kidney injury. (PMID:23324582)
• High urine alpha-1-microglobulin is associated with interstitial fibrosis and tubular atrophy plus inflammation. (PMID:23414180)
• The antioxidative protection of cells and collagen by A1M is totally dependent on its C34 amino acid residue. (PMID:23642167)
• Sulfation of the bikunin chondroitin sulfate chain determines heavy chain.hyaluronan complex formation (PMID:23801333)
• our findings suggest that urine bikunin level, as well as proteinuria, could represent a useful parameter for monitoring renal function in those patients that do not present any symptoms of renal insufficiency. (PMID:23841057)
• In pre-term pregnant women with intact membranes, placental alpha-microglobulin-1 in cervicovaginal fluid test rates are more positive in cases of uterine contraction. (PMID:23919851)
• Determined is the first structure of human alpha-1-microglobulin with heavy electron density of the chromophore. (PMID:24012674)
• The high level of serum AMBP could predict the poor response of the AGC patients. (PMID:24135868)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ambp	ENSDARG00000004296
mus_musculus	Ambp	ENSMUSG00000028356
rattus_norvegicus	Ambp	ENSRNOG00000006889
drosophila_melanogaster	CG7565	FBGN0035833
caenorhabditis_elegans		WBGENE00010792
caenorhabditis_elegans		WBGENE00015355
caenorhabditis_elegans		WBGENE00021939

Paralogs (13): TFPI (ENSG00000003436), EPPIN (ENSG00000101448), TFPI2 (ENSG00000105825), LRP11 (ENSG00000120256), WFIKKN1 (ENSG00000127578), KIAA0319 (ENSG00000137261), KIAA0319L (ENSG00000142687), SPINT4 (ENSG00000149651), WFDC8 (ENSG00000158901), SPINT1 (ENSG00000166145), SPINT2 (ENSG00000167642), WFIKKN2 (ENSG00000173714), WFDC6 (ENSG00000243543)

Protein

Protein identifiers

Protein AMBP — P02760 (reviewed: P02760)

Alternative names: Protein HC

All UniProt accessions (3): P02760, S4R3Y4, S4R471

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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. 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. Upon acute inflammation, inhibits oxidation of low-density lipoprotein particles by MPO and limits vascular damage. 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. Importantly, counteracts the oxidative damage at blood-placenta interface, preventing leakage of free fetal hemoglobin into the maternal circulation. 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. 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. Has a chaperone role in facilitating the correct folding of bikunin in the endoplasmic reticulum compartment. Kunitz-type serine protease inhibitor and structural component of extracellular matrix with a role in extracellular space remodeling and cell adhesion. 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. 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. Part of hyaluronan-rich extracellular matrix that surrounds oocyte during cumulus oophorus expansion, an indispensable process for proper ovulation. Also inhibits calcium oxalate crystallization. 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.

Subunit / interactions. Monomer. Homodimer. In plasma, it occurs as a monomer or dimer and in covalently-linked complexes with immunoglobulin A (IgA), ALB/albumin and F2/prothrombin. Chromophore-bound alpha-1-microglobulin interacts with the constant region of immunoglobulin A. 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. 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. Interacts with NDUFAB1, a subunit of mitochondrial complex I. Interacts with FN1. 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. Interacts with TNFAIP6 (via Link domain). Monomer. Also occurs as a complex with tryptase in mast cells. (Microbial infection) Interacts with hepatitis E virus/HEV protein ORF3. (Microbial infection) Interacts with hepatitis E virus/HEV protein ORF3.

Subcellular location. Secreted. Endoplasmic reticulum. Cytoplasm. Cytosol. Cell membrane. Nucleus membrane. Mitochondrion inner membrane. Extracellular space. Extracellular matrix Secreted.

Tissue specificity. Expressed by the liver and secreted in plasma. Occurs in many physiological fluids including plasma, urine, and cerebrospinal fluid. Expressed in epidermal keratinocytes, in dermis and epidermal-dermal junction (at protein level). Expressed in red blood cells (at protein level). Expressed in placenta. Detected in placenta (at protein level). Detected in cerebrospinal fluid, plasma and urine (at protein level). 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).

Post-translational modifications. The precursor is proteolytically processed into separately functioning proteins. Proteolytically cleaved in the presence of oxyhemoglobin or MPO. 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. The cleavage by MPO is associated with the transfer of heme group from MPO to t-alpha-1-microglobulin. t-alpha-1-microglobulin has higher reductase activity when compared with full length protein. 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’. Heavy chains are interlinked with bikunin via a chondroitin 4-sulfate bridge to the C-terminal aspartate. 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.

Activity regulation. 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.

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

Induction. Up-regulated upon oxidative stress. Up-regulated in keratinocytes upon exposure to heme and reactive oxygen species. Up-regulated in hemoglobin-perfused placenta. Up-regulated in airway epithelium and submucosal gland in response to inflammatory cytokine TNF.

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.

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

RefSeq proteins (1): NP_001624* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000566	Lipocln_cytosolic_FA-bd_dom	Domain
IPR002223	Kunitz_BPTI	Domain
IPR002968	A1-microglobln	Family
IPR012674	Calycin	Homologous_superfamily
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR022272	Lipocalin_CS	Conserved_site
IPR029856	AMBP	Family
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily

Pfam: PF00014, PF00061

UniProt features (71 total): strand 18, sequence conflict 11, helix 8, disulfide bond 7, glycosylation site 5, binding site 4, mutagenesis site 4, turn 4, chain 3, site 3, domain 2, signal peptide 1, region of interest 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6EJA	X-RAY DIFFRACTION	1.94
6EJ7	X-RAY DIFFRACTION	2
4ES7	X-RAY DIFFRACTION	2
6EJ9	X-RAY DIFFRACTION	2.02
6EJC	X-RAY DIFFRACTION	2.06
6EJ8	X-RAY DIFFRACTION	2.09
3QKG	X-RAY DIFFRACTION	2.3
1BIK	X-RAY DIFFRACTION	2.5
4U30	X-RAY DIFFRACTION	2.5
6EJB	X-RAY DIFFRACTION	2.56
6EJD	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02760-F1	82.03	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 199 (cleavage; in the presence of oxyhemoglobin or mpo); 241–242 (inhibitory (p1) (chymotrypsin, elastase)); 297–298 (inhibitory (p1) (trypsin))

Ligand- & substrate-binding residues (4): 149 (covalent); 53 (covalent); 111 (covalent); 137 (covalent)

Disulfide bonds (7): 91–188, 231–281, 240–264, 256–277, 287–337, 296–320, 312–333

Glycosylation sites (5): 24, 36, 115, 215, 250

Mutagenesis-validated functional residues (4):

Position	Phenotype
53	impairs the reductase activity toward cytochrome c independently of the electron donnor. decreases the reductase activit
111	impairs the reductase activity toward cytochrome c in the presence of nadph; when associated with t-137 and t-149. impai
137	impairs the reductase activity toward cytochrome c in the presence of nadph; when associated with t-111 and t-149. impai
149	impairs the reductase activity toward cytochrome c in the presence of nadph; when associated with t-111 and t-137. impai

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2168880	Scavenging of heme from plasma
R-HSA-2173782	Binding and Uptake of Ligands by Scavenger Receptors
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 174 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, MODULE_52, GNF2_GSTM1, GNF2_HPN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_118, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_JNK_CASCADE

GO Biological Process (6): cell adhesion (GO:0007155), female pregnancy (GO:0007565), protein catabolic process (GO:0030163), heme catabolic process (GO:0042167), negative regulation of JNK cascade (GO:0046329), negative regulation of immune response (GO:0050777)

GO Molecular Function (10): serine-type endopeptidase inhibitor activity (GO:0004867), oxidoreductase activity (GO:0016491), calcium channel inhibitor activity (GO:0019855), IgA binding (GO:0019862), heme binding (GO:0020037), carbohydrate binding (GO:0030246), protein homodimerization activity (GO:0042803), calcium oxalate binding (GO:0046904), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (15): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), mitochondrial inner membrane (GO:0005743), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), extracellular matrix (GO:0031012), nuclear membrane (GO:0031965), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Binding and Uptake of Ligands by Scavenger Receptors	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
intracellular membrane-bounded organelle	3
binding	2
cellular process	1
multi-organism reproductive process	1
multi-multicellular organism process	1
macromolecule catabolic process	1
protein metabolic process	1
porphyrin-containing compound catabolic process	1
heme metabolic process	1
pigment catabolic process	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
negative regulation of immune system process	1
immune response	1
negative regulation of response to stimulus	1
regulation of immune response	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
catalytic activity	1
calcium channel regulator activity	1
calcium channel activity	1
ion channel inhibitor activity	1
immunoglobulin binding	1
tetrapyrrole binding	1
identical protein binding	1
protein dimerization activity	1
carboxylic acid binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
organelle inner membrane	1
mitochondrial membrane	1
endomembrane system	1
membrane	1
cell periphery	1
external encapsulating structure	1
nucleus	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

29 interactions, top by confidence:

A	B	Type	Score
CTSB	AMBP	psi-mi:“MI:0915”(physical association)	0.600
AMBP	CTSB	psi-mi:“MI:0403”(colocalization)	0.600
AMBP	FHL3	psi-mi:“MI:0915”(physical association)	0.560
FHL3	AMBP	psi-mi:“MI:0915”(physical association)	0.560
AMBP		psi-mi:“MI:0915”(physical association)	0.530
	AMBP	psi-mi:“MI:0407”(direct interaction)	0.530
AMBP		psi-mi:“MI:0407”(direct interaction)	0.530
	VAPB	psi-mi:“MI:0914”(association)	0.500
AMBP	APP	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
	AMBP	psi-mi:“MI:0915”(physical association)	0.370
COX8A	AMBP	psi-mi:“MI:0915”(physical association)	0.370
AMBP	DAAM1	psi-mi:“MI:0915”(physical association)	0.370
AMBP	STAT3	psi-mi:“MI:0915”(physical association)	0.370
CTDP1	ESYT2	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	SERPINA1	psi-mi:“MI:0914”(association)	0.350
AMBP	PIK3R3	psi-mi:“MI:0915”(physical association)	0.000
AMBP	GRB2	psi-mi:“MI:0915”(physical association)	0.000
AMBP	PIK3CA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): FHL3 (Two-hybrid), AMBP (Affinity Capture-MS), AMBP (Affinity Capture-MS), AMBP (Two-hybrid), AMBP (Reconstituted Complex), AMBP (Co-purification), FN1 (Affinity Capture-Western), A2M (Affinity Capture-Western), A2M (Affinity Capture-Western), AMBP (Affinity Capture-MS), AMBP (Affinity Capture-Western), ALB (Affinity Capture-Western), CD79A (Affinity Capture-Western), AMBP (Affinity Capture-MS), AMBP (Affinity Capture-MS)

ESM2 similar proteins: A2AJB7, B0CLX4, H2B3G5, O08976, O18874, O55006, O95445, P00978, P02760, P02763, P02764, P04366, P04939, P06911, P07361, P09465, P14630, P19652, P21350, P21352, P25227, P29460, P35578, P36992, P43432, P46282, P46658, P48095, P68220, P68221, P81608, Q07456, Q26241, Q29147, Q29614, Q2LE37, Q2PE76, Q3SZR3, Q5R894, Q5VFH6

Diamond homologs: A0A1D0BND9, A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A8Y7N9, A8Y7P0, A8Y7P6, B1B5I8, B2BS84, B5KF95, B5KL37, B5KL38, B5L5R7, B6RLX2, B6ZIW0, C0HJF3, C0HK74, C0HLB2, C0HMC7, C1IC52, C8YJ94, D8KY58, G3LH89, H2A0N1, H2A0P0, O35536, O43278, O43291, O54819, O76840, P00978, P00990, P00991, P02760, P04365, P04366, P0DJ50

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

85 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1321 predictions. Top by Δscore:

Variant	Effect	Δscore
9:114061526:CAT:C	acceptor_gain	1.0000
9:114074164:G:C	acceptor_gain	1.0000
9:114074164:G:GC	acceptor_gain	1.0000
9:114074176:C:CT	acceptor_gain	1.0000
9:114074956:TTA:T	donor_loss	1.0000
9:114074957:TA:T	donor_loss	1.0000
9:114074958:A:AC	donor_gain	1.0000
9:114074958:ACTGG:A	donor_loss	1.0000
9:114074959:C:CA	donor_gain	1.0000
9:114074959:CT:C	donor_gain	1.0000
9:114074959:CTG:C	donor_gain	1.0000
9:114074959:CTGG:C	donor_gain	1.0000
9:114074959:CTGGA:C	donor_gain	1.0000
9:114074981:T:TA	donor_gain	1.0000
9:114074982:C:A	donor_gain	1.0000
9:114075032:CTTTC:C	acceptor_gain	1.0000
9:114075033:TTTC:T	acceptor_gain	1.0000
9:114075034:TTC:T	acceptor_gain	1.0000
9:114075035:TC:T	acceptor_gain	1.0000
9:114075036:CC:C	acceptor_gain	1.0000
9:114075037:C:CC	acceptor_gain	1.0000
9:114075037:CTA:C	acceptor_loss	1.0000
9:114078087:CCTTA:C	donor_loss	1.0000
9:114078089:TTA:T	donor_loss	1.0000
9:114078090:TA:T	donor_loss	1.0000
9:114078091:AC:A	donor_gain	1.0000
9:114078092:C:G	donor_loss	1.0000
9:114078092:CC:C	donor_gain	1.0000
9:114061528:T:TC	acceptor_gain	0.9900
9:114062755:CTCT:C	acceptor_gain	0.9900

AlphaMissense

2298 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:114060971:G:C	F327L	0.998
9:114060971:G:T	F327L	0.998
9:114060973:A:G	F327L	0.998
9:114061447:C:G	C277S	0.998
9:114061448:A:T	C277S	0.998
9:114061092:C:T	C287Y	0.997
9:114060954:C:G	C333S	0.996
9:114060955:A:T	C333S	0.996
9:114060972:A:C	F327C	0.996
9:114060977:G:C	N325K	0.996
9:114060977:G:T	N325K	0.996
9:114061017:C:G	C312S	0.996
9:114061018:A:T	C312S	0.996
9:114061092:C:G	C287S	0.996
9:114061093:A:T	C287S	0.996
9:114061435:C:G	C281S	0.996
9:114061436:A:T	C281S	0.996
9:114061446:A:C	C277W	0.996
9:114061448:A:G	C277R	0.996
9:114061464:G:C	F271L	0.996
9:114061464:G:T	F271L	0.996
9:114061466:A:G	F271L	0.996
9:114061510:C:G	C256S	0.996
9:114061510:C:T	C256Y	0.996
9:114061511:A:T	C256S	0.996
9:114076726:C:A	W44C	0.996
9:114076726:C:G	W44C	0.996
9:114076728:A:G	W44R	0.996
9:114076728:A:T	W44R	0.996
9:114060942:C:T	C337Y	0.995

dbSNP variants (sampled 300 via entrez): RS1000042054 (9:114069530 C>A,G), RS1000236290 (9:114062070 T>C), RS1000608576 (9:114065352 G>A,T), RS1000906762 (9:114076838 T>C), RS1000961170 (9:114065104 C>T), RS1001115677 (9:114071070 C>A), RS1001116529 (9:114066851 CAAT>C), RS1001365048 (9:114077169 G>C), RS1001718618 (9:114068177 C>G), RS1001766366 (9:114068443 A>C), RS1001954827 (9:114066364 C>A), RS1002014603 (9:114074310 C>T), RS1002135766 (9:114060537 T>C), RS1002335931 (9:114078327 G>A,T), RS1002366062 (9:114066134 C>T)

Disease associations

OMIM: gene MIM:176870 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression	3
sodium arsenite	decreases expression, increases expression	3
Cadmium	affects binding, affects expression, decreases expression, increases abundance	3
Tetrachlorodibenzodioxin	decreases expression, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
chloroacetaldehyde	increases expression	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
deoxynivalenol	decreases expression	1
decabromobiphenyl ether	increases expression	1
perfluorooctanoic acid	decreases expression	1
1-anilino-8-naphthalenesulfonate	affects binding	1
hydroquinone	increases expression	1
nivalenol	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
benazepril	decreases expression, increases reaction	1
11-(dansylamino)undecanoic acid	affects binding	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.