Tau protein: Wikis

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Microtubule-associated protein tau
Identifiers
Symbols MAPT; DDPAC; FLJ31424; FTDP-17; MAPTL; MGC138549; MSTD; MTBT1; MTBT2; PPND; TAU
External IDs OMIM157140 HomoloGene44834 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_005910 NM_001038609.1
RefSeq (protein) NP_005901 NP_001033698.1
Location (UCSC) Chr 17:
41.33 - 41.46 Mb
Chr 11:
103.99 - 104.19 Mb
PubMed search [1] [2]

Tau proteins are proteins that stabilize microtubules. They are abundant in neurons in the central nervous system and are less common elsewhere. When tau proteins are defective, and no longer stabilize microtubules properly, they can result in dementias, such as Alzheimer's disease.

The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT.[1][2] They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University.[3]

Contents

Function

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.

Six tau isoforms exist in 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.

Phosphorylation of tau is regulated by a host of kinases. For example, PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.[4]

Hyperphosphorylation of the tau protein (tau inclusions), however, 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.[5]

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are mostly found in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. 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 STOP proteins in the proximal portions of axons which essentially lock down the microtubules and MAP2 that stabilizes microtubules in dendrites. The tau gene locates on chromosome 17q21, containing 16 exons. The major tau protein in the human brain is encoded by 11 exons. Exon 2, 3 and 10 are alternative spliced, allowing six combinations (2-3-10-; 2+3-10-; 2+3+10-; 2-3-10+; 2+3-10+; 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 no, 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). 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.

Interactions

Tau protein has been shown to interact with FYN,[6] Alpha-synuclein,[7] YWHAZ[8] and S100B.[9][10]

See also

References

  1. ^ 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. PMID 3131773. 
  2. ^ 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. PMID 2484340. 
  3. ^ 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. PMID 1057175. 
  4. ^ 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. 
  5. ^ 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. PMID 11381127. 
  6. ^ Klein, Corinna; Kramer Eva-Maria, Cardine Anne-Marie, Schraven Burkhardt, Brandt Roland, Trotter Jacqueline (Feb. 2002). "Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau". J. Neurosci. (United States) 22 (3): 698–707. PMID 11826099. 
  7. ^ Jensen, P H; Hager H, Nielsen M S, Hojrup P, Gliemann J, Jakes R (Sep. 1999). "alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356". J. Biol. Chem. (UNITED STATES) 274 (36): 25481–9. ISSN 0021-9258. PMID 10464279. 
  8. ^ Hashiguchi, M; Sobue K, Paudel H K (Aug. 2000). "14-3-3zeta is an effector of tau protein phosphorylation". J. Biol. Chem. (UNITED STATES) 275 (33): 25247–54. doi:10.1074/jbc.M003738200. ISSN 0021-9258. PMID 10840038. 
  9. ^ Yu, W H; Fraser P E (Apr. 2001). "S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease". J. Neurosci. (United States) 21 (7): 2240–6. PMID 11264299. 
  10. ^ Baudier, J; Cole R D (Apr. 1988). "Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II". J. Biol. Chem. (UNITED STATES) 263 (12): 5876–83. ISSN 0021-9258. PMID 2833519. 

Further reading

  • Goedert M, Crowther RA, Garner CC (1991). "Molecular characterization of microtubule-associated proteins tau and MAP2". Trends Neurosci. 14 (5): 193–9. doi:10.1016/0166-2236(91)90105-4. PMID 1713721. 
  • Morishima-Kawashima M, Hasegawa M, Takio K, et al. (1995). "Hyperphosphorylation of tau in PHF". Neurobiol. Aging 16 (3): 365–71; discussion 371–80. doi:10.1016/0197-4580(95)00027-C. PMID 7566346. 
  • Heutink P (2000). "Untangling tau-related dementia". Hum. Mol. Genet. 9 (6): 979–86. doi:10.1093/hmg/9.6.979. PMID 10767321. 
  • Goedert M, Spillantini MG (2000). "Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease". Biochim. Biophys. Acta 1502 (1): 110–21. PMID 10899436. 
  • Morishima-Kawashima M, Ihara Y (2002). "[Recent advances in Alzheimer's disease]". Seikagaku 73 (11): 1297–307. PMID 11831025. 
  • Blennow K, Vanmechelen E, Hampel H (2002). "CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease". Mol. Neurobiol. 24 (1-3): 87–97. doi:10.1385/MN:24:1-3:087. PMID 11831556. 
  • Ingram EM, Spillantini MG (2003). "Tau gene mutations: dissecting the pathogenesis of FTDP-17". Trends in molecular medicine 8 (12): 555–62. doi:10.1016/S1471-4914(02)02440-1. PMID 12470988. 
  • Pickering-Brown S (2004). "The tau gene locus and frontotemporal dementia". Dementia and geriatric cognitive disorders 17 (4): 258–60. doi:10.1159/000077149. PMID 15178931. 
  • van Swieten JC, Rosso SM, van Herpen E, et al. (2004). "Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17". Dementia and geriatric cognitive disorders 17 (4): 261–4. doi:10.1159/000077150. PMID 15178932. 
  • Kowalska A, Jamrozik Z, Kwieciński H (2004). "Progressive supranuclear palsy--parkinsonian disorder with tau pathology". Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 42 (2): 119–23. PMID 15266787. 
  • Rademakers R, Cruts M, van Broeckhoven C (2005). "The role of tau (MAPT) in frontotemporal dementia and related tauopathies". Hum. Mutat. 24 (4): 277–95. doi:10.1002/humu.20086. PMID 15365985. 
  • Lee HG, Perry G, Moreira PI, et al. (2005). "Tau phosphorylation in Alzheimer's disease: pathogen or protector?". Trends in molecular medicine 11 (4): 164–9. doi:10.1016/j.molmed.2005.02.008. PMID 15823754. 
  • Hardy J, Pittman A, Myers A, et al. (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. 
  • Deutsch SI, Rosse RB, Lakshman RM (2007). "Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications". Prog. Neuropsychopharmacol. Biol. Psychiatry 30 (8): 1369–80. doi:10.1016/j.pnpbp.2006.04.007. PMID 16793187. 
  • Williams DR (2006). "Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau". Internal medicine journal 36 (10): 652–60. doi:10.1111/j.1445-5994.2006.01153.x. PMID 16958643. 
  • Pittman AM, Fung HC, de Silva R (2006). "Untangling the tau gene association with neurodegenerative disorders". Hum. Mol. Genet. 15 Spec No 2: R188–95. doi:10.1093/hmg/ddl190. PMID 16987883. 
  • Roder HM, Hutton ML (2007). "Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease". Expert Opin. Ther. Targets 11 (4): 435–42. doi:10.1517/14728222.11.4.435. PMID 17373874. 
  • van Swieten J, Spillantini MG (2007). "Hereditary frontotemporal dementia caused by Tau gene mutations". Brain Pathol. 17 (1): 63–73. doi:10.1111/j.1750-3639.2007.00052.x. PMID 17493040. 
  • Caffrey TM, Wade-Martins R (2007). "Functional MAPT haplotypes: bridging the gap between genotype and neuropathology". Neurobiol. Dis. 27 (1): 1–10. doi:10.1016/j.nbd.2007.04.006. PMID 17555970. 
  • Delacourte A (2005). "Tauopathies: recent insights into old diseases". Folia Neuropathol 43 (4): 244–57. PMID 16416389. 
  • Hirokawa N, Shiomura Y, Okabe S (October 1988). "Tau proteins: the molecular structure and mode of binding on microtubules". J. Cell Biol. 107 (4): 1449–59. PMID 3139677. 

External links

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