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microtubule-associated protein tau (neurofibrillary tangle protein, paired helical filament-tau, PHF-tau, MAPT, MTBT1, m-tau, mtau)

A family of microtubule-binding proteins Classification: - fetal (type I) - adult (type II) Function: - bind microtubules & stimulate assembly [6] - stabilization of axonal microtubules - role in establishment & maintenance of neuronal polarity - in neurons, axonal polarity is predetermined by tau localization in the domain of the cell body defined by the centrosome - short isoforms allow plasticity of the cytoskeleton; - longer isoforms may preferentially play a role in stabilization of the cytoskeleton - may link plasma membrane with cytoskeleton (microtubules) - role in signal transduction - interaction with actin cytoskeleton - neurite outgrowth - anchoring of enzymes - regulation of intracellular vesicle transport - phosphorylation - phosphorylation of tau regulates binding to microtubules [10] - phosphorylation of about 19-30 sites occurs normally - phosphorylation sites are clustered in the regions of the microtubule-binding domains - increasing tau phosphorylation within repeat domain diminishes microtubule-binding [10,11] - increasing tau phosphorylation within flanking regions diminishes plasma membrane-binding - phosphorylation on Ser-610, Ser-622, Ser-641 & Ser-673 in several isoforms during mitosis - highly phosphorylated tau associated with torpor phase of hibernation [9] - phosphorylation decreases with age - protein kinases phosphorylating tau - proline-directed kinases (PDPK: CDC2, CDK5, GSK-3, MAPK) - Ser & Thr in S-P or T-P motifs - only 2-3 sites per protein in interphase, - seven-fold increase in mitosis, & in PHF-tau - glycogen synthase kinase 3-beta (GSK-3-beta) - cyclin-dependent kinases (CDK2 & CDK5) - tau-tubulin-kinase - stress-activated protein (SAP) kinase - mitogen-activated protein (MAP) kinase - fyn kinase [8] - ds DNA-dependent protein kinase [11] - MARK (MARK1, MARK2, MARK3) [11] - at Ser in K-X-G-S motifs - PKA, PKC, CaM kinase, casein kinase 1 & 2 [11] - Protein phosphatases dephosphorylating tau: - dephosphorylated by PP1A & PP2A* [11] * Stimulation of the M1 receptor may diminish phosphorylation [7] - Proteases cleaving tau - multiple caspases (cleavage at Asp421, enhanced by A4/42) [5] - cleavage of tau by caspase 1,3,6,7,& 8 - caspase cleavage associated with formation of paired helical filaments & neurofibrillary tangles [5] - polyubiquitination - requires functional TRAF6 & may provoke SQSTM1-dependent degradation by the proteasome - interactions (other) - interacts with PSMC2 through SQSTM1 (putative) - interacts with SQSTM1 when polyubiquitinated Structure: - N-terminus binds neural plasma membrane components - C-terminus binds axonal microtubules (tubulin) - contains 3 or 4 tau/MAP repeats; the tau/MAP repeat binds to tubulin - calmodulin-binding site & 3 PEST regions - type I isoforms contain 3 tau/MAP repeats - type II isoforms contain 4 tau/MAP repeats * fibrillogenic forms of tau have shorter half-lives than non-fibrillogenic forms [18] Compartment: - cytoplasm, highly soluble [6] - cell membrane - peripheral membrane protein; cytoplasmic side - cytoskeleton - cell projection, axon - mostly found in the axons of neurons, in the cytosol & in association with plasma membrane components - released into CSF within 2 hours of neuronal activity associated with presynpatic glutamine release - 1/2 life in CSF is 11 days [17] - multiple forms of tau exist in CSF [18] - truncated forms of tau released into CSF [18] - release of tau into CSF correlates with amyloid burden [18] Alternative splicing: named isoforms=9; Additional isoforms seem to exist; isoforms differ from each other by the presence or absence of up to 5 of the 15 exons; one of these optional exons contains the additional tau/MAP repeat Expression: - expressed in neurons, mainly neuronal - PNS-tau is expressed in the peripheral nervous system; - other isoforms are expressed in the central nervous system - 4 tau/MAP repeats (type II) tau is expressed in adult brain & is not found in fetal brain, whereas - 3 tau/MAP repeats (type I) tau is found in both adult & fetal brain - expressed in low levels in astrocytes & oligodendroglia [10] Pathology: - abnormalities in tau metabolism associated with human disease are collectively referred to as tauopathies. Abnormal hyper- phosphorylation & oxidation of tau (all isoforms) occurs in the formation of paired helical filaments & straight filaments in neurofibrillary tangles, found in cortical neurons in patients with Alzheimer's disease. - mutations associated with fronto-temporal dementia with parkinsonism (FTDP) - defects associated with pallido-ponto-nigral degeneration, corticobasal degeneration (CBD), may predispose to progressive supranuclear palsy (PSP) & may be associated with hereditary dysphasic disinhibition dementia - 3 repeat isoforms predominate in Picks disease - 4 repeat isoforms predominate in FTDP-17, PSP & CBD - PHF tau is hyperphosphorylated & disulfide-linked tau dimer - glycation of PHF-tau, but not normal brain tau - glycation of tau with subsequent formation of advanced glycation endproduct may play a role in stabilizing PHF aggregation leading to tangle formation in AD - PHF-tau can be modified by three different forms of polyubiquitination - Lys-48-linked polyubiquitination is the major form - Lys-6-linked - Lys-11-linked polyubiquitination - caspase cleavage associated with formation of paired helical filaments & neurofibrillary tangles [5] - nitration of tau is found in association with neurofibrillary tangles [6] Laboratory: - microtubule-associated protein tau in CSF - phosphorylated tau in CSF - microtubule-associated protein tau in serum/plasma - phosphorylated tau in buccal swab

Interactions

molecular events

General

calmodulin binding protein microtubule-associated protein (MAP) PEST protein

Properties

QUALITIES: MICROTUBULE-ASSOCIATED SIZE: entity length = 758 aa entity length = 352-441 aa COMPARTMENT: cytoplasm MOTIF: acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl lysine residue {24} lysine residue {44} Ser phosphorylation site {S46} Thr phosphorylation site {T50} lysine residue {67} Thr phosphorylation site {T111} lysine residue {381} lysine residue {391} lysine residue {392} lysine residue {394} lysine residue {465} Thr phosphorylation site {T470} Thr phosphorylation site {T492} lysine residue {497} Thr phosphorylation site {T498} lysine residue {507} Tyr phosphorylation site {Y514} Ser phosphorylation site {S515} Ser phosphorylation site {S516} Ser phosphorylation site {S519} Thr phosphorylation site {T522} Thr phosphorylation site {T529} Ser phosphorylation site {S531} Thr phosphorylation site {T534} lysine residue {541} Thr phosphorylation site {T548} Ser phosphorylation site {S552} Ser phosphorylation site {S554} lysine residue {557} Tau/MAP {561-591} MOTIF: lysine residue {571} lysine residue {574} Ser phosphorylation site {S579} lysine residue {584} lysine residue {591} Tau/MAP {592-622} MOTIF: lysine residue {607} cysteine residue {C608} MODIFICATION: cysteine residue {C639} Ser phosphorylation site {S610} lysine residue {611} lysine residue {615} Ser phosphorylation site {S622} Tau/MAP {623-653} MOTIF: lysine residue {628} lysine residue {634} lysine residue {638} cysteine residue {C639} MODIFICATION: cysteine residue {C608} Ser phosphorylation site {S641} lysine residue {648} Tau/MAP {654-685} MOTIF: lysine residue {657} lysine residue {660} Ser phosphorylation site {S673} lysine residue {687} lysine residue {692} lysine residue {700} lysine residue {702} lysine residue {712} Ser phosphorylation site {S713} Ser phosphorylation site {S717} Thr phosphorylation site {T720} Ser phosphorylation site {S721} Ser phosphorylation site {S726} Ser phosphorylation site {S729} Thr phosphorylation site {T731} Ser phosphorylation site {S733} Ser phosphorylation site {S739} Thr phosphorylation site {T744} lysine residue {755}

Database Correlations

OMIM correlations MORBIDMAP 157140 UniProt P10636 Pfam PF00418 Entrez Gene 4137

References

  1. Wang KK et al Calmodulin-binding proteins as calpain substrates. Biochem J 262:693 1989 PMID: 2556106
  2. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989 Oct;3(4):519-26. PMID: 2484340
  3. Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 1993 Nov;16(11):460-5. Review. PMID: 7507619
  4. Entrez Gene :accession 4137
  5. Gamblin TC et al, Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A. Aug 19;100(17):10032-7. 2003 PMID: 12888622
  6. Horiguchi T et al, Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol. 2003 Sep;163(3):1021-31. Erratum in: Am J Pathol. 2003 Dec;163(6):2645. PMID: 12937143
  7. Mesulam M. The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn Mem. 2004 Jan-Feb;11(1):43-9. Review. PMID: 14747516
  8. Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal- regulated kinase: modulation by zinc. J Biol Chem. 2004 Oct 22;279(43):44795-801. Epub 2004 Aug 20. PMID: 15322121
  9. Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci. 2004 Nov;22(7):507-14. Review. PMID: 15465280
  10. Cairns NJ, Lee VM, Trojanowski JQ. The cytoskeleton in neurodegenerative diseases. J Pathol. 2004 Nov;204(4):438-49. Review. PMID: 15495240
  11. Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):298-310. Epub 2004 Nov 26. Review. PMID: 15615647
  12. UniProt :accession P10636
  13. Alzheimer research forum; Note: Tau mutations http://www.alzforum.org/res/com/mut/tau/default.asp
  14. Protein Spotlight; vita minima - Issue 68 of March 2006 http://www.expasy.org/spotlight/back_issues/sptlt068.shtml
  15. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAPT
  16. Wikipedia; Note: Tau protein entry http://en.wikipedia.org/wiki/Tau_protein
  17. Yamada K et al Neuronal activity regulates extracellular tau in vivo. Journal of Experimental Medicine. JEM. Feb 17, 2014 PMID: 24534188 http://jem.rupress.org/content/early/2014/02/11/jem.20131685.abstract
  18. George J. Do Amyloid Plaques Drive Tau Deposition? New study ties tau production to amyloid burden. MedPage Today. March 21, 2018 https://www.medpagetoday.com/neurology/alzheimersdisease/71910 - Sato C, Barthelemy NR, Mawuenyega KG Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 97(6):1284-1298. March 21, 2018 PMID: 29566794 http://www.cell.com/neuron/fulltext/S0896-6273(18)30136-3

Component-of

molecular complex