Differential Phosphorylation of Human Tau Isoforms Containing Three Repeats by Several Protein Kinases
- 作者：Singh ; Toolsee J. ; Grundke-Iqbal ; Inge ; Iqbal ; Khalid
- 刊名：Archives of Biochemistry and Biophysics
- 出版年：1996
- 期刊代码：116_00039861
- 类别：ch
- 出版时间：April 1, 1996
- 卷：328
- 期：1
- 页码：43-50
- 文件大小：172 K
摘要
The paired helical filaments (PHF) found in the brain of patients with Alzheimer disease (AD) are composed primarily of the microtubule-associated protein tau. Six isoforms of tau have been recognized and all are present in a hyperphosphorylated state in PHF. It is not known whether all tau isoforms serve equally well as substrates for various kinases. In this study we have compared the phosphorylation of human tau isoforms containing three microtubule-binding repeats and zero (τ3), one (τ3S), or two (τ3L) N-terminal inserts. Four kinases (A-kinase, CK-1, CaM kinase II, GSK-3) were used for this purpose. With A-kinase, CK-1, and CaM kinase II the extent of phosphorylation was τ3L > τ3S > τ3. With GSK-3 it was τ3L 
τ3S > τ3. Tau 3 was a poor substrate for either CaM kinase II or CK-1,32P incorporation being only 5 and 11%, respectively, of that observed by these kinases when τ3L was the substrate. After prephosphorylation of the three tau isoforms by A-kinase, a subsequent phosphorylation by GSK-3 was stimulated several fold over tau that was not prephosphorylated. Under these conditions the extent of32P incorporation was τ3L > τ3S > τ3. Both CK-1 and GSK-3 phosphorylated ser 396 more rapidly in τ3L compared to τ3 or τ3S. Our results suggest that (1) the presence of N-terminal inserts in tau isoforms are important structural determinants that modulate the specificity of several kinases; (2) the different tau isoforms may be present at different states of phosphorylation in PHF.
τ3S > τ3. Tau 3 was a poor substrate for either CaM kinase II or CK-1,32P incorporation being only 5 and 11%, respectively, of that observed by these kinases when τ3L was the substrate. After prephosphorylation of the three tau isoforms by A-kinase, a subsequent phosphorylation by GSK-3 was stimulated several fold over tau that was not prephosphorylated. Under these conditions the extent of32P incorporation was τ3L > τ3S > τ3. Both CK-1 and GSK-3 phosphorylated ser 396 more rapidly in τ3L compared to τ3 or τ3S. Our results suggest that (1) the presence of N-terminal inserts in tau isoforms are important structural determinants that modulate the specificity of several kinases; (2) the different tau isoforms may be present at different states of phosphorylation in PHF.