Uromodulin
Domain
The ZP domain mediates polymerization, leading to the formation of long filaments. The core of the filament consists of interlocked ZP domains which assemble into a helical structure. Each ZP domain consists of an N-terminal (ZP-N) and C-terminal (ZP-C) region connected by a flexible linker; the linker allows the ZP domain to wrap around the ZP-C subdomain of the preceding subunit. The heavily glycosylated N-terminal part of the protein (containing several EGF-like domains) forms branches which protrude from the core and are involved in pathogen capture.
Function
Uromodulin
Functions in biogenesis and organization of the apical membrane of epithelial cells of the thick ascending limb of Henle's loop (TALH), where it promotes formation of complex filamentous gel-like structure that may play a role in the water barrier permeability. May serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF. Facilitates neutrophil migration across renal epithelia.
Uromodulin, secreted form
In the urine, may contribute to colloid osmotic pressure, retards passage of positively charged electrolytes, and inhibits formation of liquid containing supersaturated salts and subsequent formation of salt crystals. Protects against urinary tract infections by binding to type 1 fimbriated E.coli. Binds to bacterial adhesin fimH which mediates the stable formation of bacterial aggregates, prevents the binding of E.coli to uroplakins UPK1A and UPK1B which act as urothelial receptors for type I fimbriae, and allows for pathogen clearance through micturation. Also promotes aggregation of other bacteria including K.pneumoniae, P.aeruginosa and S.mitis and so may also protect against other uropathogens.
Post-translational modifications
N-glycosylated.
Proteolytically cleaved at a conserved C-terminal proteolytic cleavage site to generate the secreted form found in urine. This cleavage is catalyzed by HPN.
Tissue Specificity
Expression restricted to the thick ascending limb of the loop of Henle (TALH).
Cellular localization
- Apical cell membrane
- Lipid-anchor
- GPI-anchor
- Basolateral cell membrane
- Lipid-anchor
- GPI-anchor
- Cell projection
- Cilium membrane
- Only a small fraction sorts to the basolateral pole of tubular epithelial cells compared to apical localization. Secreted into urine after cleavage. Colocalizes with NPHP1 and KIF3A.
- Uromodulin, secreted form
- Secreted
- Detected in urine.
Alternative names
Uromodulin, Tamm-Horsfall urinary glycoprotein, THP, Umod