microtubule-associated protein tau (neurofibrillary tangle protein, paired helical filament-tau, PHF-tau, MAPT, MTBT1)
Jump to navigation
Jump to search
Introduction
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]
- PKA, PKC, CaM kinase, casein kinase 1 & 2[11]
- proline-directed kinases (PDPK: CDC2, CDK5, GSK-3, MAPK)
- 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]
- multiple caspases (cleavage at Asp421, enhanced by A4/42)[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
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
- PHF-tau can be modified by three different forms of 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
- microtubule-associated protein tau in serum/plasma
- phosphorylated tau in buccal swab
More general terms
More specific terms
- microtubule-associated protein tau (fetal isoform)
- microtubule-associated protein tau, long splice form
- paired helical filament (PHF) tau
Additional terms
References
- ↑ Wang KK et al Calmodulin-binding proteins as calpain substrates. Biochem J 262:693 1989 PMID: https://www.ncbi.nlm.nih.gov/pubmed/2556106
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/2484340
- ↑ Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 1993 Nov;16(11):460-5. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7507619
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4137
- ↑ 5.0 5.1 5.2 5.3 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: https://www.ncbi.nlm.nih.gov/pubmed/12888622
- ↑ 6.0 6.1 6.2 6.3 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: https://www.ncbi.nlm.nih.gov/pubmed/12937143
- ↑ 7.0 7.1 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: https://www.ncbi.nlm.nih.gov/pubmed/14747516
- ↑ 8.0 8.1 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: https://www.ncbi.nlm.nih.gov/pubmed/15322121
- ↑ 9.0 9.1 Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci. 2004 Nov;22(7):507-14. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15465280
- ↑ 10.0 10.1 10.2 10.3 Cairns NJ, Lee VM, Trojanowski JQ. The cytoskeleton in neurodegenerative diseases. J Pathol. 2004 Nov;204(4):438-49. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15495240
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 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: https://www.ncbi.nlm.nih.gov/pubmed/15615647
- ↑ UniProt http://www.uniprot.org/uniprot/P10636.html
- ↑ Alzheimer research forum; Note: Tau mutations http://www.alzforum.org/res/com/mut/tau/default.asp
- ↑ Protein Spotlight; vita minima - Issue 68 of March 2006 http://www.expasy.org/spotlight/back_issues/sptlt068.shtml
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAPT
- ↑ Wikipedia; Note: Tau protein entry http://en.wikipedia.org/wiki/Tau_protein
- ↑ 17.0 17.1 Yamada K et al Neuronal activity regulates extracellular tau in vivo. Journal of Experimental Medicine. JEM. Feb 17, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24534188 <Internet> http://jem.rupress.org/content/early/2014/02/11/jem.20131685.abstract
- ↑ 18.0 18.1 18.2 18.3 18.4 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29566794 <Internet> http://www.cell.com/neuron/fulltext/S0896-6273(18)30136-3
Database
- UniProt: http://www.uniprot.org/uniprot/P10636.html
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4137
- OMIM: https://mirror.omim.org/entry/157140
- OMIM: https://mirror.omim.org/entry/172700
- OMIM: https://mirror.omim.org/entry/260540
- OMIM: https://mirror.omim.org/entry/600274
- OMIM: https://mirror.omim.org/entry/601104
- OMIM: https://mirror.omim.org/entry/607485