Tamm–Horsfall protein
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The Tamm–Horsfall glycoprotein (THP), also known as uromodulin, is a glycoprotein that in humans is encoded by the UMOD gene.[1][2] Uromodulin is the most abundant protein excreted in ordinary urine.[3]
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.[2]
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.[3] 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).[4] It is the matrix of urinary casts derived from the secretion of renal tubular cells.
3D structure
The crystal structure of UMOD (PDB: 4WRN) was reported In January 2016 by researchers at Karolinska Institutet, in collaboration with groups at San Raffaele Scientific Institute and European Synchrotron Radiation Facility.[5]
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.[2]
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.[6] 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.[3] THP may also be important in protection from kidney injury by down-regulating inflammation.[7]
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.[3]
Defects in this gene are associated with the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN). These disorders are characterized by juvenile onset of hyperuricemia, gout, and progressive kidney failure.[2]
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.[8]
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 contain Tamm–Horsfall protein.[9][10]
History
The glycoprotein was first purified in 1952 by Igor Tamm and Frank Horsfall from the urine of healthy individuals.[11] It was later detected in the urine of all mammals studied.
References
- ↑ Jeanpierre C, Whitmore SA, Austruy E, Cohen-Salmon M, Callen DF, Junien C (Mar 1993). "Chromosomal assignment of the uromodulin gene (UMOD) to 16p13.11". Cytogenet Cell Genet. 62 (4): 185–7. doi:10.1159/000133470. PMID 8382593.
- ↑ 2.0 2.1 2.2 2.3 "Entrez Gene: UMOD uromodulin (uromucoid, Tamm–Horsfall glycoprotein)".
- ↑ 3.0 3.1 3.2 3.3 Lau WH, Leong WS, Ismail Z, Gam LH (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". Int. J. Biol. Sci. 4 (4): 215–22. doi:10.7150/ijbs.4.215. PMC 2500153. PMID 18695745.
- ↑ Nagaraj N, Mann M (February 2011). "Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome". J. Proteome Res. 10 (2): 637–45. doi:10.1021/pr100835s. PMID 21126025.
- ↑ 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. doi:10.1073/pnas.1519803113. PMC 4760807. PMID 26811476. PDB: 4WRN
- ↑ Bachmann S, Mutig K, Bates J, Welker P, Geist B, Gross V, Luft FC, Alenina N, Bader M, Thiele BJ, Prasadan K, Raffi HS, Kumar S (2005). "Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice". Am. J. Physiol. Renal Physiol. 288 (3): F559–67. doi:10.1152/ajprenal.00143.2004. PMID 15522986.
- ↑ El-Achkar TM, Wu XR, Rauchman M, McCracken R, Kiefer S, Dagher PC. Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am J Physiol Renal Physiol. 2008 Aug;295(2):F534-44. doi: 10.1152/ajprenal.00083.2008. Epub 2008 May 21. PMID 18495803
- ↑ Vizjak A, Trnacević S, Ferluga D, Halilbasić A (November 1991). "Renal function, protein excretion, and pathology of Balkan endemic nephropathy. IV. Immunohistology". Kidney Int. Suppl. 34: S68–74. PMID 1762338.
- ↑ 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. p. 353. ISBN 0-7216-0265-7.
- ↑ Aster JC (2007). "The Hematopoietic and Lymphoid Systems". In Kumar V, Abbas AK, Fauso N, Mitchell R. Robbins Basic Patholog (8th ed.). Philadelphia, PA: Saunders/Elsevier. p. 455. ISBN 1-4160-2973-7.
- ↑ Tamm I, Horsfall FL (January 1952). "A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses". J. Exp. Med. 95 (1): 71–97. doi:10.1084/jem.95.1.71. PMC 2212053. PMID 14907962.
Further reading
- Scolari F, Viola BF, Ghiggeri GM, et al. (2003). "Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease". J. Nephrol. 16 (3): 321–8. PMID 12832729.
- Rindler MJ, Naik SS, Li N, et al. (1991). "Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein". J. Biol. Chem. 265 (34): 20784–9. PMID 2249987.
- Muchmore AV, Decker JM (1985). "Uromodulin: a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women". Science. 229 (4712): 479–81. doi:10.1126/science.2409603. PMID 2409603.
- Pennica D, Kohr WJ, Kuang WJ, et al. (1987). "Identification of human uromodulin as the Tamm-Horsfall urinary glycoprotein". Science. 236 (4797): 83–8. doi:10.1126/science.3453112. PMID 3453112.
- Hession C, Decker JM, Sherblom AP, et al. (1987). "Uromodulin (Tamm-Horsfall glycoprotein): a renal ligand for lymphokines". Science. 237 (4821): 1479–84. doi:10.1126/science.3498215. PMID 3498215.
- Prasadan K, Bates J, Badgett A, et al. (1995). "Nucleotide sequence and peptide motifs of mouse uromodulin (Tamm-Horsfall protein)--the most abundant protein in mammalian urine". Biochim. Biophys. Acta. 1260 (3): 328–32. doi:10.1016/0167-4781(94)00240-4. PMID 7873609.
- Huang ZQ, Kirk KA, Connelly KG, Sanders PW (1994). "Bence Jones proteins bind to a common peptide segment of Tamm-Horsfall glycoprotein to promote heterotypic aggregation". J. Clin. Invest. 92 (6): 2975–83. doi:10.1172/JCI116920. PMC 288501. PMID 8254051.
- Rhodes DC, Hinsman EJ, Rhodes JA (1994). "Tamm-Horsfall glycoprotein binds IgG with high affinity". Kidney Int. 44 (5): 1014–21. doi:10.1038/ki.1993.343. PMID 8264130.
- Fukushima K, Watanabe H, Takeo K, et al. (1993). "N-linked sugar chain structure of recombinant human lymphotoxin produced by CHO cells: the functional role of carbohydrate as to its lectin-like character and clearance velocity". Arch. Biochem. Biophys. 304 (1): 144–53. doi:10.1006/abbi.1993.1332. PMID 8323280.
- Thomas DB, Davies M, Peters JR, Williams JD (1993). "Tamm Horsfall protein binds to a single class of carbohydrate specific receptors on human neutrophils". Kidney Int. 44 (2): 423–9. doi:10.1038/ki.1993.260. PMID 8397318.
- Badgett A, Kumar S (1999). "Phylogeny of Tamm-Horsfall protein". Urol. Int. 61 (2): 72–5. doi:10.1159/000030292. PMID 9873244.
- van Rooijen JJ, Voskamp AF, Kamerling JP, Vliegenthart JF (1999). "Glycosylation sites and site-specific glycosylation in human Tamm-Horsfall glycoprotein". Glycobiology. 9 (1): 21–30. doi:10.1093/glycob/9.1.21. PMID 9884403.
- Scolari F, Puzzer D, Amoroso A, et al. (1999). "Identification of a new locus for medullary cystic disease, on chromosome 16p12". Am. J. Hum. Genet. 64 (6): 1655–60. doi:10.1086/302414. PMC 1377908. PMID 10330352.
- Kamatani N, Moritani M, Yamanaka H, et al. (2000). "Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family". Arthritis Rheum. 43 (4): 925–9. doi:10.1002/1529-0131(200004)43:4<925::AID-ANR26>3.0.CO;2-B. PMID 10765940.
- Pirulli D, Puzzer D, De Fusco M, et al. (2002). "Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12". J. Nephrol. 14 (5): 392–6. PMID 11730273.
- Menozzi FD, Debrie AS, Tissier JP, et al. (2002). "Interaction of human Tamm-Horsfall glycoprotein with Bordetella pertussis toxin". Microbiology. 148 (Pt 4): 1193–201. doi:10.1099/00221287-148-4-1193. PMID 11932463.
- Zbikowska HM, Soukhareva N, Behnam R, et al. (2002). "Uromodulin promoter directs high-level expression of biologically active human alpha1-antitrypsin into mouse urine". Biochem. J. 365 (Pt 1): 7–11. doi:10.1042/BJ20020643. PMC 1222653. PMID 11982485.
- Hart TC, Gorry MC, Hart PS, et al. (2003). "Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy". J. Med. Genet. 39 (12): 882–92. doi:10.1136/jmg.39.12.882. PMC 1757206. PMID 12471200.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
External links
- GeneReviews/NCBI/NIH/UW entry on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
- OMIM entries on UMOD-Related Kidney Disease Includes: Familial Juvenile Hyperuricemic Nephropathy, Medullary Cystic Kidney Disease 2
- Tamm–Horsfall protein deposition[permanent dead link]