PXDN
Developmental stage
Expressed in fetal liver and spleen.
Domain
The VWFC domain mediates the covalent links between monomers through disulfide bridges (PubMed:25713063). Ig-like C2-type domains are required to sulfilimine bond formation (PubMed:26178375). The VWFC domain is not required for trimerization (PubMed:31295557). The LRR domain mediates high affinity binding to laminin-1 (PubMed:32485152).
Function
Catalyzes the two-electron oxidation of bromide by hydrogen peroxide and generates hypobromite as a reactive intermediate which mediates the formation of sulfilimine cross-links between methionine and hydroxylysine residues within an uncross-linked collagen IV/COL4A1 NC1 hexamer (PubMed:18929642, PubMed:19590037, PubMed:22842973, PubMed:25708780, PubMed:25713063, PubMed:27697841, PubMed:28154175, PubMed:34679700). In turns, directly contributes to the collagen IV network-dependent fibronectin/FN and laminin assembly, which is required for full extracellular matrix (ECM)-mediated signaling (PubMed:19590037, PubMed:32543734, PubMed:34679700). Thus, sulfilimine cross-links are essential for growth factor-induced cell proliferation and survival in endothelial cells, an event essential to basement membrane integrity (PubMed:32543734). In addition, through the bromide oxidation, may promote tubulogenesis and induce angiogenesis through ERK1/2, Akt, and FAK pathways (PubMed:25713063). Moreover brominates alpha2 collagen IV chain/COL4A2 at 'Tyr-1485' and leads to bromine enrichment of the basement membranes (PubMed:32571911). In vitro, can also catalyze the two-electron oxidation of thiocyanate and iodide and these two substrates could effectively compete with bromide and thus inhibit the formation of sulfilimine bonds (PubMed:28154175). Binds laminins (PubMed:32485152). May play a role in the organization of eyeball structure and lens development during eye development (By similarity).
Involvement in disease
Anterior segment dysgenesis 7
ASGD7
A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. ASGD7 is an autosomal recessive disease.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Glycosylated (PubMed:25713063). Four sites are completely N-glycosylated (Asn-640, Asn-731, Asn-865 and Asn-1425), whereas the others are found partially glycosylated (PubMed:25713063).
Processed by FURIN and the proteolytic processing largely depends on the peroxidase activity of PXDN (PubMed:27697841, PubMed:34679700). The proteolytic cleavage occurs after intracellular homotrimerization and releases into the extracellular matrix a large, catalytically active fragment and a smaller fragment consisting primarily of the C-terminal VWFC domain (PubMed:27697841, PubMed:31295557). The processing enhances both peroxidase activity and sulfilimine cross-links formation (PubMed:27697841, PubMed:34679700).
Sequence Similarities
Belongs to the peroxidase family. XPO subfamily.
Tissue Specificity
Expressed at higher levels in heart, lung, ovary, spleen, intestine and placenta, and at lower levels in liver, colon, pancreas, kidney, thymus, skeletal muscle and prostate. Expressed in tumors such as melanoma, breast cancer, ovarian cancer and glioblastoma. A shorter form probably lacking the signal sequence is found in testis and in EB1 cells undergoing p53/TP53-dependent apoptosis.
Cellular localization
- Secreted
- Extracellular space
- Extracellular matrix
- Endoplasmic reticulum
- Cell surface
- Secreted
- Extracellular space
- Extracellular matrix
- Basement membrane
- Enriched in the peritubular space of fibrotic kidneys. Adheres on the cell surface in 'hot spots' (PubMed:25708780). Only the proteolytically processed PXDN integrates into the extracellular matrix (PubMed:34679700).
- PXDN active fragment
- Secreted
- Extracellular space
- Extracellular matrix
Alternative names
KIAA0230, MG50, PRG2, PXD01, VPO, VPO1, PXDN, Peroxidasin homolog, Melanoma-associated antigen MG50, Peroxidasin 1, Vascular peroxidase 1, p53-responsive gene 2 protein, hsPxd01