SUBUNIT: Interacts with PSMC2 through SQSTM1 (By similarity). Interacts with SQSTM1 when polyubiquitinated. Interacts with FKBP4 (By similarity).
SUBCELLULAR LOCATION: Cytoplasm, cytosol. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cytoplasm, cytoskeleton. Cell projection, axon. Note=Mostly found in the axons of neurons, in the cytosol and in association with plasma membrane components.
ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=9; Comment=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; Name=PNS-tau; IsoId=P10636-1; Sequence=Displayed; Name=Fetal-tau; IsoId=P10636-2; Sequence=VSP_003176, VSP_003177, VSP_003179, VSP_003180, VSP_003181; Name=Tau-A; IsoId=P10636-3; Sequence=VSP_003175, VSP_003176, VSP_003177, VSP_003178, VSP_003179, VSP_003180, VSP_003181; Name=Tau-B; IsoId=P10636-4; Sequence=VSP_003177, VSP_003179, VSP_003180, VSP_003181; Name=Tau-C; Synonyms=Tau-3; IsoId=P10636-5; Sequence=VSP_003179, VSP_003180, VSP_003181; Name=Tau-D; IsoId=P10636-6; Sequence=VSP_003176, VSP_003177, VSP_003179, VSP_003180; Name=Tau-E; IsoId=P10636-7; Sequence=VSP_003177, VSP_003179, VSP_003180; Name=Tau-F; Synonyms=Tau-4; IsoId=P10636-8; Sequence=VSP_003179, VSP_003180; Name=Tau-G; IsoId=P10636-9; Sequence=VSP_026780; Note=No experimental confirmation available;
TISSUE SPECIFICITY: Expressed in neurons. Isoform PNS-tau is expressed in the peripheral nervous system while the others are expressed in the central nervous system. DEVELOPMENTAL STAGE: Four-repeat (type II) tau is expressed in an adult-specific manner and is not found in fetal brain, whereas three-repeat (type I) tau is found in both adult and fetal brain.
DOMAIN: The tau/MAP repeat binds to tubulin. Type I isoforms contain 3 repeats while type II isoforms contain 4 repeats.
PTM: Phosphorylation at serine and threonine residues in S-P or T- P motifs by proline-directed protein kinases (PDPK: CDK1, CDK5, GSK-3, MAPK) (only 2-3 sites per protein in interphase, seven-fold increase in mitosis, and in PHF-tau), and at serine residues in K- X-G-S motifs by MAP/microtubule affinity-regulating kinase (MARK) in Alzheimer diseased brains. Phosphorylation decreases with age. Phosphorylation within tau's repeat domain or in flanking regions seems to reduce tau's interaction with, respectively, microtubules or plasma membrane components. Phosphorylation on Ser-610, Ser- 622, Ser-641 and Ser-673 in several isoforms during mitosis. Phosphorylation at Ser-579 by BRSK1 and BRSK2 in neurons affects ability to bind microtubules and plays a role in neuron polarization.
PTM: Polyubiquitinated. Requires functional TRAF6 and may provoke SQSTM1-dependent degradation by the proteasome (By similarity). PHF-tau can be modified by three different forms of polyubiquitination. 'Lys-48'-linked polyubiquitination is the major form, 'Lys-6'-linked and 'Lys-11'-linked polyubiquitination also occur.
PTM: Glycation of PHF-tau, but not normal brain tau. Glycation is a non-enzymatic post-translational modification that involves a covalent linkage between a sugar and an amino group of a protein molecule forming ketoamine. Subsequent oxidation, fragmentation and/or cross-linking of ketoamine leads to the production of advanced glycation endproducts (AGES). Glycation may play a role in stabilizing PHF aggregation leading to tangle formation in AD.
DISEASE: Note=In Alzheimer disease, the neuronal cytoskeleton in the brain is progressively disrupted and replaced by tangles of paired helical filaments (PHF) and straight filaments, mainly composed of hyperphosphorylated forms of TAU (PHF-TAU or AD P- TAU).
DISEASE: Defects in MAPT are a cause of frontotemporal dementia (FTD) [MIM:600274]; also called frontotemporal dementia (FTD), pallido-ponto-nigral degeneration (PPND) or historically termed Pick complex. This form of frontotemporal dementia is characterized by presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.
DISEASE: Defects in MAPT are a cause of Pick disease of the brain (PIDB) [MIM:172700]. It is a rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration.
DISEASE: Note=Defects in MAPT are a cause of corticobasal degeneration (CBD). It is marked by extrapyramidal signs and apraxia and can be associated with memory loss. Neuropathologic features may overlap Alzheimer disease, progressive supranuclear palsy, and Parkinson disease.
DISEASE: Defects in MAPT are a cause of progressive supranuclear palsy type 1 (PSNP1) [MIM:601104]; also abbreviated as PSP and also known as Steele-Richardson-Olszewski syndrome. PSNP1 is characterized by akinetic-rigid syndrome, supranuclear gaze palsy, pyramidal tract dysfunction, pseudobulbar signs and cognitive capacities deterioration. Neurofibrillary tangles and gliosis but no amyloid plaques are found in diseased brains. Most cases appear to be sporadic, with a significant association with a common haplotype including the MAPT gene and the flanking regions. Familial cases show an autosomal dominant pattern of transmission with incomplete penetrance; genetic analysis of a few cases showed the occurrence of tau mutations, including a deletion of Asn-613.
DISEASE: Defects in MAPT are a cause of Parkinson-dementia syndrome (PARDE) [MIM:260540]. A syndrome characterized by parkinsonism tremor, rigidity, dementia, ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration occurs in the hippocampus, basal ganglia and brainstem nuclei.
SIMILARITY: Contains 4 Tau/MAP repeats. WEB RESOURCE: Name=Alzheimer Research Forum; Note=Tau mutations; URL="http://www.alzforum.org/res/com/mut/tau/default.asp"; WEB RESOURCE: Name=Protein Spotlight; Note=Vita minima - Issue 68 of March 2006; URL="http://web.expasy.org/spotlight/back_issues/sptlt068.shtml"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAPT"; WEB RESOURCE: Name=Wikipedia; Note=Tau protein entry; URL="http://en.wikipedia.org/wiki/Tau_protein";
GENE SYNONYMS: MAPTL MTBT1 TAU.
COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.