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Combinatorial Tau Pseudophosphorylation: Markedly Different Regulatory Effects on Microtubule Assembly and Dynamic Instability than the Sum of the Individual Parts

Kiris, Erkan and Ventimiglia, Donovan and Sargin, Mehmet E. and Gaylord, Michelle R. and Altinok, Alphan and Rose, Kenneth and Manjunath, B. S. and Jordan, Mary Ann and Wilson, Leslie and Feinstein, Stuart C. (2011) Combinatorial Tau Pseudophosphorylation: Markedly Different Regulatory Effects on Microtubule Assembly and Dynamic Instability than the Sum of the Individual Parts. Journal of Biological Chemistry, 286 (16). pp. 14257-14270. ISSN 0021-9258. PMCID PMC3077627. https://resolver.caltech.edu/CaltechAUTHORS:20110504-073756239

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Abstract

Tau is a multiply phosphorylated protein that is essential for the development and maintenance of the nervous system. Errors in Tau action are associated with Alzheimer disease and related dementias. A huge literature has led to the widely held notion that aberrant Tau hyperphosphorylation is central to these disorders. Unfortunately, our mechanistic understanding of the functional effects of combinatorial Tau phosphorylation remains minimal. Here, we generated four singly pseudophosphorylated Tau proteins (at Thr^(231), Ser^(262), Ser^(396), and Ser^(404)) and four doubly pseudophosphorylated Tau proteins using the same sites. Each Tau preparation was assayed for its abilities to promote microtubule assembly and to regulate microtubule dynamic instability in vitro. All four singly pseudophosphorylated Tau proteins exhibited loss-of-function effects. In marked contrast to the expectation that doubly pseudophosphorylated Tau would be less functional than either of its corresponding singly pseudophosphorylated forms, all of the doubly pseudophosphorylated Tau proteins possessed enhanced microtubule assembly activity and were more potent at regulating dynamic instability than their compromised singly pseudophosphorylated counterparts. Thus, the effects of multiple pseudophosphorylations were not simply the sum of the effects of the constituent single pseudophosphorylations; rather, they were generally opposite to the effects of singly pseudophosphorylated Tau. Further, despite being pseudophosphorylated at different sites, the four singly pseduophosphorylated Tau proteins often functioned similarly, as did the four doubly pseudophosphorylated proteins. These data lead us to reassess the conventional view of combinatorial phosphorylation in normal and pathological Tau action. They may also be relevant to the issue of combinatorial phosphorylation as a general regulatory mechanism.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1074/jbc.M111.219311DOIArticle
http://www.jbc.org/content/286/16/14257.abstractPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077627/PubMed CentralArticle
Additional Information:© 2011 American Society for Biochemistry and Molecular Biology. Received for publication, January 6, 2011 Published, JBC Papers in Press, February 2, 2011. This work was supported, in whole or in part, by National Institutes of Health Grants NS-35010 (to S. C. F.), NS-13560 (to L. W.), and CA-57291 (to M. A. J.). This work was also supported by National Science Foundation Grant ITR-0331697 (to B. S. M., K. R., S. C. F., and L. W.). We are very grateful to Herb Miller for generously providing superb tubulin and axonemes. We are also grateful to Jack Reifert for generating the T231D construct and proteins, to Doug Thrower for assistance with the dynamics protocols, to Brian Matsumoto for help with microscopy, and to Bob Jacobs for sharing the ultracentrifuge.
Funders:
Funding AgencyGrant Number
NIHNS-35010
NIHNS-13560
NIHCA-57291
NSFITR-0331697
Issue or Number:16
PubMed Central ID:PMC3077627
Record Number:CaltechAUTHORS:20110504-073756239
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110504-073756239
Official Citation:Combinatorial Tau Pseudophosphorylation: Markedly Different Regulatory Effects on Microtubule Assembly and Dynamic Instability than the Sum of the Individual Parts. J. Biol. Chem. 2011 286: 14257-14270. First Published on February 2, 2011, doi:10.1074/jbc.M111.219311
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23541
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:06 May 2011 15:33
Last Modified:03 Oct 2019 02:47

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