Tau蛋白

Tau蛋白
已知的结构 PDB 直系同源搜索：PDBe RCSB PDBID列表 1I8H、4GLR、2ON9、3OVL、4E0M、4E0N、4E0O、4FL5、4NP8、2MZ7、4TQE、4Y5I、4Y32、5DMG、4Y3B、5HF3、5E2W、5E2V
标识符
代号	MAPT
扩展标识	OMIM：157140；MGI：97180；HomoloGene：74962；GeneCards：MAPT；OMA：MAPT - orthologs
基因位置（人类） 染色体 17號染色體 基因座 17q21.31 起始 45,894,527 bp 终止 46,028,334 bp
基因位置（小鼠） 染色体 小鼠11号染色体 基因座 11 67.79 cM|11 E1 起始 104,231,390 bp 终止 104,332,090 bp
RNA表达模式 Bgee 人类 小鼠（直系同源） Top expressed in right frontal lobe right hemisphere of cerebellum Brodmann area 9 hippocampus proper Top expressed in lateral septal nucleus central gray substance of midbrain CA3 field nucleus of stria terminalis 查阅更多表达数据 BioGPS 查阅更多表达数据
基因本體 分子功能 apolipoprotein binding SH3 domain binding tubulin binding 血浆蛋白结合 lipoprotein particle binding 酶结合 DNA结合 actin binding microtubule binding dynactin binding receptor ligand activity protein phosphatase 2A binding Hsp90 protein binding minor groove of adenine-thymine-rich DNA binding double-stranded DNA binding single-stranded DNA binding RNA binding protein kinase binding protein-macromolecule adaptor activity phosphatidylinositol binding 相同蛋白质结合 protein homodimerization activity sequence-specific DNA binding chaperone binding histone-dependent DNA binding microtubule lateral binding phosphatidylinositol bisphosphate binding 細胞組分 細胞質 cell body cell projection nuclear periphery 生长锥 神經纖維糾纏 细胞膜 tubulin complex 树突 cytoplasmic ribonucleoprotein granule 细胞骨架 细胞核 细胞质基质 微管 microtubule associated complex 膜 nuclear speck 轴突 somatodendritic compartment soma axon cytoplasm 細胞外區域 胞內 線粒體 microtubule cytoskeleton axolemma neuron projection 树突棘 main axon 脂筏模型 glial cell projection 生物學過程 generation of neurons regulation of autophagy regulation of microtubule polymerization positive regulation of microtubule polymerization positive regulation of axon extension microtubule cytoskeleton organization microglial cell activation activation of cysteine-type endopeptidase activity involved in apoptotic process 訊息傳遞 記憶 negative regulation of mitochondrial membrane potential axonal transport of mitochondrion cytoplasmic microtubule organization neuron projection development positive regulation of superoxide anion generation negative regulation of kinase activity cellular response to heat astrocyte activation intracellular distribution of mitochondria synapse organization regulation of calcium-mediated signaling protein complex oligomerization plus-end-directed organelle transport along microtubule regulation of mitochondrial fission negative regulation of mitochondrial fission 軸突運輸 regulation of cellular response to heat positive regulation of neuron death positive regulation of protein localization to synapse neurofibrillary tangle assembly negative regulation of establishment of protein localization to mitochondrion positive regulation of diacylglycerol kinase activity regulation of response to DNA damage stimulus internal protein amino acid acetylation cell-cell signaling response to lead ion regulation of signaling receptor activity negative regulation of gene expression rRNA metabolic process central nervous system neuron development regulation of microtubule polymerization or depolymerization regulation of chromosome organization stress granule assembly cellular response to reactive oxygen species microtubule polymerization regulation of synaptic plasticity axon development regulation of microtubule cytoskeleton organization supramolecular fiber organization regulation of long-term synaptic depression positive regulation of protein localization negative regulation of tubulin deacetylation amyloid fibril formation cellular response to nerve growth factor stimulus cellular response to brain-derived neurotrophic factor stimulus 来源：Amigo / QuickGO
直系同源 物種 人類 小鼠 Entrez 4137 17762 Ensembl ENSG00000186868 ​ENSG00000276155 ​ENSG00000277956 ENSMUSG00000018411 UniProt P10636 P10637 mRNA序列 NM_001123066 ​NM_001123067 ​NM_001203251 ​NM_001203252 ​NM_005910 ​NM_016834 ​NM_016835 ​NM_016841 ​NM_001377265 ​NM_001377266 ​NM_001377267 ​NM_001377268 NM_001038609 ​NM_010838 ​NM_001285454 ​NM_001285455 ​NM_001285456 蛋白序列 NP_001116538 ​NP_001116539 ​NP_001190180 ​NP_001190181 ​NP_005901 ​NP_058518 ​NP_058519 ​NP_058525 ​NP_001364194 ​NP_001364195 ​NP_001364196 ​NP_001364197 NP_001033698 ​NP_001272383 ​NP_001272384 ​NP_001272385 ​NP_034968 ​NP_001390904 ​NP_001390905 ​NP_001390906 ​NP_001390907 ​NP_001390908 ​NP_001390909 ​NP_001390910 ​NP_001390911 ​NP_001390912 ​NP_001390913 ​NP_001390916 ​NP_001390919 ​NP_001390921 ​NP_001390923 ​NP_001390925 ​NP_001390927 ​NP_001390928 ​NP_001390931 ​NP_001390933 ​NP_001390934 ​NP_001390935 ​NP_001390939 ​NP_001390940 ​NP_001390941 ​NP_001390943 ​NP_001390944 ​NP_001390945 基因位置 Chr 17：45.89 – 46.03 Mb Chr 11：104.23 – 104.33 Mb PubMed查询
维基数据
檢視/編輯人類 檢視/編輯小鼠

tau蛋白（tau proteins）或作τ蛋白、濤蛋白，化学式为：C₃₃₈₄H₅₄₇₁O₁₁₄₃N₉₉₇S₁₂，是一种广泛存在于神经元轴突与胞体中的微管相关细胞骨架蛋白。在正常生理情况下，tau蛋白多与微管蛋白相结合，有促进微管聚合和稳定的作用。术语“tau”是 tubulin associated unit（微管蛋白相关单位）的缩写。

tau蛋白属于一种低分子量微管相关蛋白，在中枢神经系统的神经元非常丰富而少见于其它细胞，但在中枢神经系统的星形胶质细胞和少突胶质细胞中表达量也很低。在病理状态下，tau蛋白呈过磷酸化，从微管上解离并变为不溶性，形成双螺旋状或直的神经原纤维（neurofibril），导致神经原纤维缠结（neurofibrillary tangles）形成，与神经系统病变（阿兹海默病）相关。

tau蛋白的多种蛋白异型体是由单个基因（人类基因组中为 MAPT，microtubule-associated protein tau，微管相关蛋白tau）mRNA的選擇性剪接而形成的。1975年，它们由Marc Kirschner在普林斯顿大学的实验室中发现。

功能

tau蛋白是一种高度可溶的微管相关蛋白（MAP）。与非神经元细胞相较，人体内tau更多地在神经元内发现。tau蛋白的主要功能之一是维持轴突微管的稳定性。而其它神经系统中的MAPs家族蛋白也有着相似的功能，这体现在tau敲除的小鼠并没有发现其脑组织的发育受到影响。这可能是在tau缺失后，其它MAPs家族蛋白在神经元内起到代偿tau的作用，从而继续维持轴突微管的稳定，保证脑功能的正常运作。tau并不在树突发挥功能，而主要作用在轴突远端维持微管的稳定性和必要的灵活性。这与MAP6蛋白（位于轴突近端固定微管）与MAP2（主要维持树突的稳定性）的功能相对。

Tau蛋白与微管蛋白（Tubulin）相互作用以稳定微管，同时驱动Tubulin在微管内组装。Tau蛋白通过异构和磷酸化控制微管的稳定性。

结构

六tau蛋白异构体存在于人类脑部组织中，以在结合区域中的编号为标识。其中三个异构体拥有三个结合区域，其余三个异构体则有四个。此结合区域位于该蛋白的羟基末端并带有正电（可与带负电的微管结合）。而带有四个结合区域的异构体有更好的稳定微管的功能。此异构体则为tau基因的2、3和10号外显子被选择性剪切的产物。

tau蛋白可视为一个在最长的tau蛋白异构体上拥有79个丝氨酸和苏氨酸磷酸化位点的磷酸蛋白。有报道称磷酸蛋白在普通tau蛋白的这些位点上的数量已达到30个左右。

磷酸蛋白同时也受激酶宿主的控制，包括PKN（丝氨酸/苏氨酸蛋白激酶）。当PKN被激活，便会磷酸化tau蛋白从而造成微管组织破坏。

tau蛋白的磷酸蛋白也被先天性地控制。例如婴儿中枢神经系统的tau蛋白的磷酸化程度比成人的更高。而所有异构体中的磷酸化程度由于磷酸酶的作用会随着人年龄的增长而减弱。比如激酶，磷酸酶也在对这个tau蛋白的磷酸蛋白的调节中起到作用。

临床意义

tau蛋白（tau包含物，pTau）的过磷酸化可导致配对的螺旋丝和直丝的缠结的自组装，其参与阿茲海默病，额颞叶痴呆，和其他tau蛋白病的发病机理。

另见

• Tau蛋白病变，一类与tau蛋白积累有关的疾病
• 慢性創傷性腦病變 (Chronic traumatic encephalopathy, CTE)
• 拳击员痴呆
• 阿兹海默病
• 皮质基地变性
• Template:进行性核上性麻痹
• 蛋白质构象病
• 皮克氏病
• 17号染色体额颞叶痴呆症和帕金森氏症
• 朊病毒

扩展阅读

• Goedert M, Crowther RA, Garner CC. Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci. 1991, 14 (5): 193–9. PMID 1713721. doi:10.1016/0166-2236(91)90105-4. 
• Morishima-Kawashima M, Hasegawa M, Takio K; et al. Hyperphosphorylation of tau in PHF. Neurobiol. Aging. 1995, 16 (3): 365–71; discussion 371–80. PMID 7566346. doi:10.1016/0197-4580(95)00027-C.  引文格式1维护：显式使用等标签 (link)
• Heutink P. Untangling tau-related dementia. Hum. Mol. Genet. 2000, 9 (6): 979–86. PMID 10767321. doi:10.1093/hmg/9.6.979. 
• Goedert M, Spillantini MG. Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease. Biochim. Biophys. Acta. 2000, 1502 (1): 110–21. PMID 10899436. doi:10.1016/S0925-4439(00)00037-5. 
• Morishima-Kawashima M, Ihara Y. [Recent advances in Alzheimer's disease]. Seikagaku. 2002, 73 (11): 1297–307. PMID 11831025. 
• Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. Mol. Neurobiol. 2002, 24 (1–3): 87–97. PMID 11831556. doi:10.1385/MN:24:1-3:087. 
• Ingram EM, Spillantini MG. Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends in molecular medicine. 2003, 8 (12): 555–62. PMID 12470988. doi:10.1016/S1471-4914(02)02440-1. 
• Pickering-Brown S. The tau gene locus and frontotemporal dementia. Dementia and geriatric cognitive disorders. 2004, 17 (4): 258–60. PMID 15178931. doi:10.1159/000077149. 
• van Swieten JC, Rosso SM, van Herpen E; et al. Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17. Dementia and geriatric cognitive disorders. 2004, 17 (4): 261–4. PMID 15178932. doi:10.1159/000077150.  引文格式1维护：显式使用等标签 (link)
• Kowalska A, Jamrozik Z, Kwieciński H. Progressive supranuclear palsy--parkinsonian disorder with tau pathology. Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences. 2004, 42 (2): 119–23. PMID 15266787. 
• Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. Mutat. 2005, 24 (4): 277–95. PMID 15365985. doi:10.1002/humu.20086. 
• Lee HG, Perry G, Moreira PI; et al. Tau phosphorylation in Alzheimer's disease: pathogen or protector?. Trends in molecular medicine. 2005, 11 (4): 164–9. PMID 15823754. doi:10.1016/j.molmed.2005.02.008.  引文格式1维护：显式使用等标签 (link)
• Hardy J, Pittman A, Myers A; et al. Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens. Biochem. Soc. Trans. 2005, 33 (Pt 4): 582–5. PMID 16042549. doi:10.1042/BST0330582.  引文格式1维护：显式使用等标签 (link)
• Deutsch SI, Rosse RB, Lakshman RM. 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. 2007, 30 (8): 1369–80. PMID 16793187. doi:10.1016/j.pnpbp.2006.04.007. 
• Williams DR. Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Internal medicine journal. 2006, 36 (10): 652–60. PMID 16958643. doi:10.1111/j.1445-5994.2006.01153.x. 
• Pittman AM, Fung HC, de Silva R. Untangling the tau gene association with neurodegenerative disorders. Hum. Mol. Genet. 15. 2006,. Spec No 2 (Review Issue 2): R188–95. PMID 16987883. doi:10.1093/hmg/ddl190. 
• Roder HM, Hutton ML. Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease. Expert Opin. Ther. Targets. 2007, 11 (4): 435–42. PMID 17373874. doi:10.1517/14728222.11.4.435. 
• van Swieten J, Spillantini MG. Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathol. 2007, 17 (1): 63–73. PMID 17493040. doi:10.1111/j.1750-3639.2007.00052.x. 
• Caffrey TM, Wade-Martins R. Functional MAPT haplotypes: bridging the gap between genotype and neuropathology. Neurobiol. Dis. 2007, 27 (1): 1–10. PMC 2801069 . PMID 17555970. doi:10.1016/j.nbd.2007.04.006. 
• Delacourte A. Tauopathies: recent insights into old diseases. Folia Neuropathol. 2005, 43 (4): 244–57. PMID 16416389. 
• Hirokawa N, Shiomura Y, Okabe S. Tau proteins: the molecular structure and mode of binding on microtubules. J. Cell Biol. October 1988, 107 (4): 1449–59. PMC 2115262 . PMID 3139677. doi:10.1083/jcb.107.4.1449. 

外部链接

• 醫學主題詞表（MeSH）：tau+Proteins
• GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders（页面存档备份，存于互联网档案馆）
• MR scans of variant CJD CSF Tau positive man