Uromodulin

Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a Zona pellucida-like domain-containing glycoprotein that in humans is encoded by the UMOD gene.[5][6] Uromodulin is the most abundant protein excreted in ordinary urine.[7]

UMOD
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesUMOD, ADMCKD2, FJHN, HNFJ, HNFJ1, MCKD2, THGP, THP, uromodulin, ADTKD1
External IDsOMIM: 191845 MGI: 102674 HomoloGene: 2522 GeneCards: UMOD
Orthologs
SpeciesHumanMouse
Entrez

7369

22242

Ensembl

ENSG00000169344

ENSMUSG00000030963

UniProt

P07911

Q91X17

RefSeq (mRNA)

NM_001278605
NM_009470

RefSeq (protein)

NP_001265534
NP_033496

Location (UCSC)Chr 16: 20.33 – 20.36 MbChr 7: 119.06 – 119.08 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

The human UMOD gene is located on chromosome 16. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode the same isoform.[6]

Protein

THP is a GPI-anchored glycoprotein. It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney. While the monomeric molecule has a MW of approximately 85 kDa, it is physiologically present in urine in large aggregates of up to several million Da.[7] When this protein is concentrated at low pH, it forms a gel. Uromodulin represents the most abundant protein in normal human urine (results based on MSMS determinations).[8] It is the matrix of urinary casts derived from the secretion of renal tubular cells.

Structure

Uromodulin consists of an EGF domain (EGF I); two calcium-binding EGF domains (EGF II, III); a cysteine-rich decoy module consisting of a β-hairpin and a D10C domain (previously referred to as D8C); a fourth EGF domain; and a C-terminal bipartite Zona pellucida-like (ZP) module consisting of ZP-N and ZP-C domains separated by an interdomain linker.[9][10] The ZP domain polymerizes into filaments,[11] with protruding arms that correspond to the EGF I-III domains and the decoy module.[10][12][13][14]

Function

Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. Uromodulin may act as a constitutive inhibitor of calcium crystallization in renal fluids. The excretion of uromodulin in urine may provide defense against urinary tract infections caused by uropathogenic bacteria.[6]

The function of THP is not well understood. Studies using THP deficient mice revealed that THP may have a role in regulatory physiology and actually participates in transporter function.[15] A role in bacterial binding and sequestration is suggested by studies showing that Escherichia coli which express MS (mannose-sensitive) pili or fimbriae (also fimbria, from the Latin word for "fringe") can be trapped by Tamm–Horsfall protein via its mannose-containing side chains.[7] THP may also be important in protection from kidney injury by down-regulating inflammation.[16]

Clinical significance

Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing kidney stones or calculus. Tamm–Horsfall protein is part of the matrix in renal calculi but a role in kidney stone formation remains debatable. However, decreased levels of Tamm–Horsfall in urine have been found to be a good indicator of kidney stones.[7]

Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and autosomal dominant tubulointerstitial kidney disease (ADTKD) (previously familial juvenile hyperuricemic nephropathy (FJHN)). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive kidney failure.[6]

Antibodies to Tamm–Horsfall protein have been seen in various forms of nephritis (e.g., Balkan nephropathy), however, it remains unclear whether there is any pathophysiologic relevance to these findings.[17]

Another disease associated with mutations in this gene is Uromodulin-associated Kidney Disease (UKD), a rare autosomal dominant progressive failure of the kidneys.

In multiple myeloma, there is often protein cast in the distal convoluted tubule and collecting duct of the kidneys, mainly consisting of immunoglobulin light chain known as Bence Jones protein, but often also containing Tamm–Horsfall protein.[18][19] This is known as myeloma cast nephropathy.

History

The glycoprotein was first purified in 1950 by Igor Tamm and Frank Horsfall from the urine of healthy individuals.[20] It was later detected in the urine of all mammals studied.

References
  1. GRCh38: Ensembl release 89: ENSG00000169344 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000030963 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C (March 1993). "Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11". Cytogenetics and Cell Genetics. 62 (4): 185–7. doi:10.1159/000133470. PMID 8382593.
  6. "Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein)".
  7. Lau WH, Leong WS, Ismail Z, Gam LH (August 2008). "Qualification and application of an ELISA for the determination of Tamm Horsfall protein (THP) in human urine and its use for screening of kidney stone disease". International Journal of Biological Sciences. 4 (4): 215–22. doi:10.7150/ijbs.4.215. PMC 2500153. PMID 18695745.
  8. Nagaraj N, Mann M (February 2011). "Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome". Journal of Proteome Research. 10 (2): 637–45. doi:10.1021/pr100835s. PMID 21126025.
  9. Bokhove M, Nishimura K, Brunati M, Han L, de Sanctis D, Rampoldi L, Jovine L (2016). "A structured interdomain linker directs self-polymerization of human uromodulin". Proc. Natl. Acad. Sci. U.S.A. 113 (6): 1552–1557. Bibcode:2016PNAS..113.1552B. doi:10.1073/pnas.1519803113. PMC 4760807. PMID 26811476. PDB: 4WRN​
  10. Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L (2022). "Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH". Nat. Struct. Mol. Biol. 29 (3): 190–193. doi:10.1038/s41594-022-00729-3. PMC 8930769. PMID 35273390. PDB: 7PFP, 7Q3N​
  11. Jovine L, Qi H, Williams Z, Litscher E, de Sanctis D, Wassarman PM (2002). "The ZP domain is a conserved module for polymerization of extracellular proteins". Nat. Cell Biol. 4 (6): 457–461. doi:10.1038/ncb802. PMID 12021773. S2CID 11575790.
  12. Stsiapanava A, Xu C, Brunati M, Zamora-Caballero S, Schaeffer C, Bokhove M, Han L, Hebert H, Carroni M, Yasumasu S, Rampoldi L, Wu B, Jovine L (2020). "Cryo-EM structure of native human uromodulin, a zona pellucida module polymer". EMBO J. 39 (24): e106807. doi:10.15252/embj.2020106807. PMC 7737619. PMID 33196145. bioRxiv 10.1101/2020.05.28.119206 PDB: 6TQK, 6TQL​
  13. Weiss GL, Stanisich JJ, Sauer MM, Lin CW, Eras J, Zyla DS, Trück J, Devuyst O, Aebi M, Pilhofer M, Glockshuber R (2020). "Architecture and function of human uromodulin filaments in urinary tract infections". Science. New York, N.Y. 369 (6506): 1005–1010. doi:10.1126/science.aaz9866. PMID 32616672. S2CID 220328267.
  14. Stanisich JJ, Zyla DS, Afanasyev P, Xu J, Kipp A, Olinger E, Devuyst O, Pilhofer M, Boehringer D, Glockshuber R (2020). "The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism". eLife. 9: e60265. doi:10.7554/eLife.60265. PMC 7486124. PMID 32815518. PDB: 6ZS5, 6ZYA​
  15. Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, et al. (March 2005). "Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice". American Journal of Physiology. Renal Physiology. 288 (3): F559-67. doi:10.1152/ajprenal.00143.2004. PMID 15522986. S2CID 33703271.
  16. El-Achkar TM, Wu XR, Rauchman M, McCracken R, Kiefer S, Dagher PC (August 2008). "Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression". American Journal of Physiology. Renal Physiology. 295 (2): F534-44. doi:10.1152/ajprenal.00083.2008. PMC 5504389. PMID 18495803.
  17. Vizjak A, Trnacević S, Ferluga D, Halilbasić A (November 1991). "Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology". Kidney International. 34: S68-74. PMID 1762338.
  18. Abbas AK, Gerber R, Mitchell RS, Kumar V, Fausto N (2006). Pocket companion to Robbins and Cotran Pathologic Basis of Disease (7th ed.). Philadelphia, Pa: Saunders, Elsevier. pp. 353. ISBN 0-7216-0265-7.
  19. Aster JC (2007). "The Hematopoietic and Lymphoid Systems". In Kumar V, Abbas AK, Fauso N, Mitchell R (eds.). Robbins Basic Patholog (8th ed.). Philadelphia, PA: Saunders/Elsevier. p. 455. ISBN 978-1-4160-2973-1.
  20. Tamm I, Horsfall FL (January 1952). "A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses". The Journal of Experimental Medicine. 95 (1): 71–97. doi:10.1084/jem.95.1.71. PMC 2212053. PMID 14907962.

Further reading
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