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Differential effect of phosphorylation and substrate modulation on tau's ability to promote microtubule growth and nucleation
Journal article   Open access   Peer reviewed

Differential effect of phosphorylation and substrate modulation on tau's ability to promote microtubule growth and nucleation

Roland Brandt, Gloria Lee, David B Teplow, David Shalloway and Mossad Abdel-Ghany
The Journal of biological chemistry, Vol.269(16), pp.11776-11782
04/22/1994
DOI: 10.1016/S0021-9258(17)32639-X
PMID: 8163474
url
https://doi.org/10.1016/S0021-9258(17)32639-XView
Published (Version of record) Open Access

Abstract

The neuronal microtubule-associated protein tau promotes microtubule assembly and has been implicated in the development of axonal morphology. To study the effect of phosphorylation and substrate modulation on tau's distinct activities to promote growth of existing microtubules and nucleation of new ones, we phosphorylated bacterially expressed human tau by cAMP-dependent protein kinase in the absence or presence of heparin, an acidic substrate modulator. We found that heparin increased phosphorylation of tau by a factor of more than 2 and produced tau bands with decreased electrophoretic mobility. We demonstrate that phosphorylation of tau in the absence or presence of heparin similarly reduced tau's activity to promote microtubule growth, whereas tau's activity to promote microtubules was suppressed much more after phosphorylation in the presence of heparin. Using recombinant tau fragments we showed that heparin-induced phosphorylation caused a specific shift in electrophoretic mobility indicative of a change in tau's conformation. By aminoterminal sequencing of a tau fragment starting at residue 154 we provide evidence that phosphorylation of serine 156 is responsible for this mobility shift and for the effect on tau's nucleation activity. We conclude that tau's activities to promote growth of existing microtubules and nucleation of new ones are differentially affected by the phosphorylation of specific tau residues. Regulation of the phosphorylation state by substrate modulation may play an important role in regulating tau's function.
 Phosphorylation Cyclic AMP-Dependent Protein Kinases - metabolism Recombinant Proteins - metabolism Amino Acid Sequence Escherichia coli Humans Microtubules - physiology Recombinant Proteins - chemistry tau Proteins - metabolism Peptide Fragments - pharmacology Phosphoserine - metabolism tau Proteins - isolation & purification tau Proteins - chemistry Recombinant Proteins - isolation & purification Tubulin - metabolism Cloning, Molecular Protein Conformation Kinetics Heparin - pharmacology

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