Abstract. In a previous report we have shown that microtubule-associated protein tau can be induced to form paracrystals (Lichtenberg, B., E.-M. Mandelkow, T. Hagestedt, and E. . Nature [Lond.]. 334:359-362). A striking feature was the high degree of elasticity of the molecules. We now report that this property is related to the state of phosphorylation. When tau is dephosphorylated by alkaline phosphatase, it becomes shorter and more elastic; when it is phosphorylated by Ca++/calmodulin-dependent kinase, it becomes longer and stiffer. This may provide a model for the control of structural properties of tau-like molecules by phosphorylation.T AU is one of the microtubule-associated proteins (MAPs)' in mammalian brain (Weingarten et al., 1975). When isolated from brain tissue it is a mixture of several polypeptides of apparent molecule mass values between 50 and 70 kD. The sequence oftau protein from mouse containing 364 amino acid residues has been reported (Lee et al., 1988a). A highly homologous human form oftau has been found in the neurofibrillary tangles of Alzheimer's disease (Goedert et al., 1988). The COOH-terminal part oftau contains three internal repeats and seems to be responsible for the binding to microtubules (Aizawa et al., 1988). This part is also homologous to the COOH-terminal region of microtubule-associated protein 2 (MAP2), another brain MAP (Lewis et all., 1988), suggesting that it might serve as a microtubule-binding domain for a family of proteins.Tau is heat stable and soluble in perchloric acid (Cleveland et al., 1977;Lindwall and Cole, 1984b); this forms the basis for the isolation procedure (see Materials and Methods). Cole and co-workers showed that the apparent heterogeneity oftau can be reduced by controlling the state of phosphorylation (Lindwall and Cole, 1984b;Baudier and Cole, 1987a). Tan treated by alkaline phosphatase shows four main isoforms on SDS gels, termed taul--4. All of them can be phosphorylated by several kinases. In particular, the Ca++/calmodulin-dependent kinase (CaMK) induces a conformational change that results in an upward shift of the bands in the gel. Thus, when the protein is isolated in a mixed state of phosphorylation the number of observed bands is greater than four. The change in electrophoretic mobility is a convenient assay to monitor phosphorylation by CaMK; it is not observed 1. Abbreviations used in this paper: CaMK, Ca++/calmodulin-dependent protein kinase; MAP, microtubule-associated protein; MAP2, microtubuleassociated protein 2.after phosphorylation with other kinases such as protein kinase C.Structural information on tau or other MAPs is limited so far. Hydrodynamic data (Cleveland et al., 1977) and metal shadowing (Hirokawa et al., 1988) suggest a rod-like shape. In our attempts to crystallize tau we have recently obtained paracrystals suitable for electron microscopy and image processing (Lichtenberg et al., 1988). They show distinct transverse banding and polarity, indicating that the protein subunits are aligned with the same orientation...
Tau is one of the diverse group of microtubule-associated proteins that bind to microtubules and may thereby influence their structure and function. It occurs in the mammalian brain, mainly in axons, and is a component of the neurofibrillary tangles of Alzheimer's disease. Tau was recently sequenced, but there remains a short-age of structural data on the protein. We have now prepared paracrystals of tau suitable for electron microscopy and image processing. They show distinct transverse banding and polarity, indicating that the protein subunits are aligned with the same orientations. In contrast to other paracrystals, those of tau protein can stretch or contract continuously by more than three-fold; the axial repeats range from 22 to 68 nm. After scaling to a common period, the density distributions are closely superimposable. This suggests that tau is an elastic molecule.
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