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Microtubule-associated protein tau
PDB 1i8h EBI.jpg
Rendering of a fragment of MAPT bound to the WW domain of the PIN1 protein from PDB 1I8H
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MAPT ; DDPAC; FTDP-17; MAPTL; MSTD; MTBT1; MTBT2; PPND; PPP1R103; TAU
External IDs OMIM157140 HomoloGene74962 ChEMBL: 1293224 GeneCards: MAPT Gene
RNA expression pattern
PBB GE MAPT 203929 s at tn.png
PBB GE MAPT 203928 x at tn.png
PBB GE MAPT 203930 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4137 17762
Ensembl ENSG00000186868 ENSMUSG00000018411
UniProt P10636 P10637
RefSeq (mRNA) NM_001123066 NM_001038609
RefSeq (protein) NP_001116538 NP_001033698
Location (UCSC) Chr 17:
43.97 – 44.11 Mb
Chr 11:
104.23 – 104.33 Mb
PubMed search [1] [2]

Tau proteins (or τ proteins, after the Greek letter by that name) are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.[1] Pathologies and dementias of the nervous system such as Alzheimer's disease can result when tau proteins become defective and no longer stabilize microtubules properly.

The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT (microtubule-associated protein tau).[2][3] They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University.[4]

Function[edit]

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knockout mice that did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs.[5] Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of axons, which, in essence, lock down the microtubules and MAP2 that stabilizes microtubules in dendrites.

Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.

Structure[edit]

Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively-charged (allowing it to bind to the negatively-charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2, 3, and 10 of the tau gene.

Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.[6]

Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.[7]

Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[8] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.[9] Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396.[10] The binding of these phosphatases to tau affects tau's association with MTs.

Genetics[edit]

The MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons.[citation needed] The major tau protein in the human brain is encoded by 11 exons.[citation needed] Exons 2, 3 and 10 are alternatively spliced, allowing six combinations (2310; 2+310; 2+3+10; 2310+; 2+310+; 2+3+10+). Thus, in the human brain, the tau proteins constitute a family of six isoforms with the range from 352-441 amino acids. They differ in either zero, one or two inserts of 29 amino acids at the N-terminal part (exon 2 and 3), and three or four repeat-regions at the C-terminal part exon 10 missing. So, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).

The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copy of the gene, resulting in congenital defects.[11][12][13][14]

Role in disease[edit]

Further information: Tauopathy

Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease and other tauopathies.[15]

All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.

Recent research suggests that tau may be released extracellularly by an exosome based mechanism in Alzheimer's disease.[16][17]

Some aspects of how the disease functions also suggests that it has some similarities to prion proteins.[18]

Traumatic brain injury[edit]

High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma.[19]

Interactions[edit]

Tau protein has been shown to interact with proto-oncogene tyrosine-protein kinase FYN,[20] Alpha-synuclein,[21][22] YWHAZ[23] and S100B.[24][25]

See also[edit]

References[edit]

  1. ^ Shin RW, Iwaki T, Kitamoto T, Tateishi J (May 1991). "Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues". Lab. Invest. 64 (5): 693–702. PMID 1903170. 
  2. ^ Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (June 1988). "Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau". Proc. Natl. Acad. Sci. U.S.A. 85 (11): 4051–5. doi:10.1073/pnas.85.11.4051. PMC 280359. PMID 3131773. 
  3. ^ Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (October 1989). "Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease". Neuron 3 (4): 519–26. doi:10.1016/0896-6273(89)90210-9. PMID 2484340. 
  4. ^ Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (May 1975). "A protein factor essential for microtubule assembly". Proc. Natl. Acad. Sci. U.S.A. 72 (5): 1858–62. doi:10.1073/pnas.72.5.1858. PMC 432646. PMID 1057175. 
  5. ^ Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N (June 1994). "Altered microtubule organization in small-calibre axons of mice lacking tau protein". Nature 369 (6480): 488–91. doi:10.1038/369488a0. PMID 8202139. 
  6. ^ Billingsley ML, Kincaid RL (May 1997). "Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration". Biochem. J. 323 (3): 577–91. PMC 1218358. PMID 9169588. 
  7. ^ Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C (March 2001). "Phosphorylation of tau is regulated by PKN". J. Biol. Chem. 276 (13): 10025–31. doi:10.1074/jbc.M007427200. PMID 11104762. 
  8. ^ Kanemaru K, Takio K, Miura R, Titani K, Ihara Y (May 1992). "Fetal-type phosphorylation of the tau in paired helical filaments". J. Neurochem. 58 (5): 1667–75. doi:10.1111/j.1471-4159.1992.tb10039.x. PMID 1560225. 
  9. ^ Mawal-Dewan M, Henley J, Van de Voorde A, Trojanowski JQ, Lee VM (December 1994). "The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases". J. Biol. Chem. 269 (49): 30981–7. PMID 7983034. 
  10. ^ Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O'Connor M, Trojanowski JQ, Lee VM (October 1994). "Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau". Neuron 13 (4): 989–1002. doi:10.1016/0896-6273(94)90264-X. PMID 7946342. 
  11. ^ Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos AC, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP (September 2006). "Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability". Nat. Genet. 38 (9): 1032–7. doi:10.1038/ng1858. PMID 16906163. 
  12. ^ Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, Graves TA, Kidd JM, Cheng Z, Abouelleil A, Chen L, Wallis J, Glasscock J, Wilson RK, Reily AD, Duckworth J, Ventura M, Hardy J, Warren WC, Eichler EE (September 2008). "Evolutionary toggling of the MAPT 17q21.31 inversion region". Nat. Genet. 40 (9): 1076–83. doi:10.1038/ng.193. PMC 2684794. PMID 19165922. 
  13. ^ Almos PZ, Horváth S, Czibula A, Raskó I, Sipos B, Bihari P, Béres J, Juhász A, Janka Z, Kálmán J (November 2008). "H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population". Heredity (Edinb) 101 (5): 416–9. doi:10.1038/hdy.2008.70. PMID 18648385. 
  14. ^ Hardy J, Pittman A, Myers A, Gwinn-Hardy K, Fung HC, de Silva R, Hutton M, Duckworth J (August 2005). "Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens". Biochem. Soc. Trans. 33 (Pt 4): 582–5. doi:10.1042/BST0330582. PMID 16042549. 
  15. ^ Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (June 2001). "Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments". Proc. Natl. Acad. Sci. U.S.A. 98 (12): 6923–8. doi:10.1073/pnas.121119298. PMC 34454. PMID 11381127. 
  16. ^ Hall, G.F. (2011) Tau misprocessing leads to non-classical tau secretion via vesicle release – implications for the spreading of tau lesions in AD Int Conf. Alz Dis. meeting Paris, France
  17. ^ Saman, S. and Hall, G. F. (2011) Tau secretion from M1C human neuroblastoma cells occurs via the release of exosomes. Keystone Meeting on Neurodegenerative diseases, Feb 2011, Taos NM
  18. ^ Hall GF, Patuto BA (July 2012). "Is tau ready for admission to the prion club?". Prion 6 (3): 223–33. doi:10.4161/pri.19912. PMC 3399531. PMID 22561167. 
  19. ^ Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, Zipfel GJ, Stocchetti N, Brody DL (November 2011). "Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury". Brain 135 (4): 1268–80. doi:10.1093/brain/awr286. PMC 3326246. PMID 22116192. Lay summaryWashington University in St. Louis. 
  20. ^ Klein C, Kramer EM, Cardine AM, Schraven B, Brandt R, Trotter J (February 2002). "Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau". J. Neurosci. 22 (3): 698–707. PMID 11826099. 
  21. ^ Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (September 1999). "alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356". J. Biol. Chem. 274 (36): 25481–9. doi:10.1074/jbc.274.36.25481. PMID 10464279. 
  22. ^ Giasson BI, Lee VM, Trojanowski JQ (2003). "Interactions of amyloidogenic proteins". Neuromolecular Med. 4 (1–2): 49–58. doi:10.1385/NMM:4:1-2:49. PMID 14528052. 
  23. ^ Hashiguchi M, Sobue K, Paudel HK (August 2000). "14-3-3zeta is an effector of tau protein phosphorylation". J. Biol. Chem. 275 (33): 25247–54. doi:10.1074/jbc.M003738200. PMID 10840038. 
  24. ^ Yu WH, Fraser PE (April 2001). "S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease". J. Neurosci. 21 (7): 2240–6. PMID 11264299. 
  25. ^ Baudier J, Cole RD (April 1988). "Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II". J. Biol. Chem. 263 (12): 5876–83. PMID 2833519. 

Further reading[edit]

External links[edit]

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