Tau protein
The microtubule system is a neural cytoskeleton component that can participate in a variety of cellular functions. Microtubules are composed of tubulin and microtubule-related proteins, and Tau protein is the highest content of microtubule-related proteins. The cellular function of Tau protein in normal brain is to bind to tubulin to promote its polymerization to form microtubules; to bind to the formed microtubules to maintain the stability of microtubules, reduce the dissociation of tubulin molecules, and induce microtubules to bundle. The Tau protein gene is located on the long arm of chromosome 17. In normal people, six isoforms can be expressed due to different ways of editing Tau protein mRNA. Tau protein is a phosphate-containing protein, and Tau protein molecules in normal mature brains contain 2 to 3 phosphate groups. Tau protein in the brain of patients with Alzheimer's disease (Alzheimer's disease) is abnormally hyperphosphorylated. Each molecule of Tau protein can contain 5-9 phosphate groups and lose normal biological functions.
Abnormal phosphorylation of tau protein
The total amount of Tau protein in the brain of AD patients is higher than that of normal people, and the normal Tau protein is reduced and the abnormally hyperphosphorylated Tau protein is increased significantly. After the abnormal over phosphorylation of Tau protein in the brain of AD patients, the binding force to tubulin is only 1/10 of that of normal Tau protein. It also loses its biological function of promoting the formation of microtubule assembly and the role of maintaining microtubule stability. PHF- Tau competes with tubulin for binding to normal Tau protein and other macromolecular microtubule-related proteins, and seizing these proteins from microtubules leads to depolymerization of microtubules, disrupting the normal microtubule system, and abnormally phosphorylated Tau proteins aggregate themselves PHF / NFT structure. The microtubule structure of the affected neurons in the brain of AD patients is extensively destroyed, normal axonal transport is impaired, causing loss of synaptic neuronal function damage, and neurodegeneration of the brain occurs. Three Tau proteins were found in the brain of AD patients, namely cytosolic normal Tau protein (C-Tau), water-soluble abnormally phosphorylated Tau protein (AD p-Tau) and abnormally modified Tau protein (PHF- Tau), which is ubiquitin-modified.
Tau tubulin kinase (TTBK)
Tau tubulin kinase is a protein in the human body that is encoded by the TTBK gene. The gene encodes a serine-threonine kinase, which is speculated to phosphorylate tau and tubulin. Mutations in this gene cause type 11 spinal cerebellar ataxia (SCA11). A neurodegenerative disease characterized by progressive ataxia and atrophy of the cerebellum and brainstem. Tau-tubulin kinase (TTBK) belongs to the casein kinase superfamily, which phosphorylates the tubulin-associated protein tau and tubulin. TTBK has two isoforms, TTBK1 and TTBK2, which contain highly homologous catalytic domains, but their non-catalytic domains are significantly different. TTBK1 is specifically expressed in the central nervous system and is involved in the phosphorylation and aggregation of tau. TTBK2 is universally expressed in a variety of tissues and is linked to type 11 spinal cerebellar ataxia genes. TTBK1 directly phosphorylates tau proteins, especially Ser422, and activates cyclin-dependent kinase 5 in a unique mechanism. In two populations in China and Spain, the expression of TTBK1 protein in the brain of Alzheimer's disease (AD) is significantly increased, and genetic variation of the TTBK1 gene is associated with delayed Alzheimer's disease. When TTBK1 transgenic mice carrying the complete 55-base genomic sequence of human TTBK1 were crossed with tau mutant mice, they showed tau accumulation, neuroinflammation, and neurodegenerative progression.
Tau-Tubulin kinases family
The TTBK series consists of TTBK1 and TTBK2. These two kinases belong to the casein kinase 1 (CK1) group, which contains CK1 (α1, α2, γ1, γ2, γ3, δ, and ε), TTBK (1 and 2), and vaccinia-related kinase (VRK) 1-3. CK1δ phosphorylates tau in cultured cells and is upregulated in AD brain. The alignment of TTBK1 and CK1δ kinase domains shows 38% identity and 52% similarity; therefore, TTBK1 is the closest relative of CK1, but is not a member of the CK1 family. The catalytic domain of TTBK1 is conserved in vertebrates, C. elegans and D. melanogaster. In TTBK1 14-577 and TTBK2 1-589 regions, the amino acid sequences of TTBK1 and TTBK2 have 60% identity and 71% similarity. Their kinase domains (TTBK1 35–294 and TTBK2 21–280) are highly homologous (88% identity, 96% similarity). Except for the small domain, the remaining sequences have no homology (TTBK1 1053–1117 and TTBK2 942–1006 have 43% homology and 58% similarity). In zebrafish to human vertebrates, the preservation of TTBK1 and TTBK2 is significantly different. However, the TTBK homologues in C. elegans (TTBK), Clostridium cephalosporin (TTBK1), and D. melanogaster (ASATOR) retain only the catalytic domains of TTBK1 or TTBK2. Because the catalytic domains of TTBK1 and TTBK2 are highly homologous, this suggests that the TTBK1 and TTBK2 genes differ from the common shorter TTBK genes in the evolution from invertebrates to vertebrates.
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