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The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35

In a series of studies, we have identified TFP5, a truncated fragment of p35, the Cdk5 kinase regulatory protein, which inhibits Cdk5/p35 and the hyperactive Cdk5/p25 activities in test tube experiments. In cortical neurons, however, and in vivo in Alzheimer’s disease (AD) model mice, the peptide sp...

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Autores principales: Amin, Niranjana D., Zheng, Yali, BK, Binukumar, Shukla, Varsha, Skuntz, Susan, Grant, Philip, Steiner, Joseph, Bhaskar, Manju, Pant, Harish C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170856/
https://www.ncbi.nlm.nih.gov/pubmed/27630261
http://dx.doi.org/10.1091/mbc.E15-12-0857
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author Amin, Niranjana D.
Zheng, Yali
BK, Binukumar
Shukla, Varsha
Skuntz, Susan
Grant, Philip
Steiner, Joseph
Bhaskar, Manju
Pant, Harish C.
author_facet Amin, Niranjana D.
Zheng, Yali
BK, Binukumar
Shukla, Varsha
Skuntz, Susan
Grant, Philip
Steiner, Joseph
Bhaskar, Manju
Pant, Harish C.
author_sort Amin, Niranjana D.
collection PubMed
description In a series of studies, we have identified TFP5, a truncated fragment of p35, the Cdk5 kinase regulatory protein, which inhibits Cdk5/p35 and the hyperactive Cdk5/p25 activities in test tube experiments. In cortical neurons, however, and in vivo in Alzheimer’s disease (AD) model mice, the peptide specifically inhibits the Cdk5/p25 complex and not the endogenous Cdk5/p35. To account for the selective inhibition of Cdk5/p25 activity, we propose that the “p10” N-terminal domain of p35, absent in p25, spares Cdk5/p35 because p10 binds to macromolecules (e.g., tubulin and actin) as a membrane-bound multimeric complex that favors p35 binding to Cdk5 and catalysis. To test this hypothesis, we focused on Munc 18, a key synapse-associated neuronal protein, one of many proteins copurifying with Cdk5/p35 in membrane-bound multimeric complexes. Here we show that, in vitro, the addition of p67 protects Cdk5/p35 and has no effect on Cdk5/p25 activity in the presence of TFP5. In cortical neurons transfected with p67siRNA, we also show that TFP5 inhibits Cdk5/p35 activity, whereas in the presence of p67 the activity is protected. It does so without affecting any other kinases of the Cdk family of cyclin kinases. This difference may be of significant therapeutic value because the accumulation of the deregulated, hyperactive Cdk5/p25 complex in human brains has been implicated in pathology of AD and other neurodegenerative disorders.
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spelling pubmed-51708562017-01-16 The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35 Amin, Niranjana D. Zheng, Yali BK, Binukumar Shukla, Varsha Skuntz, Susan Grant, Philip Steiner, Joseph Bhaskar, Manju Pant, Harish C. Mol Biol Cell Articles In a series of studies, we have identified TFP5, a truncated fragment of p35, the Cdk5 kinase regulatory protein, which inhibits Cdk5/p35 and the hyperactive Cdk5/p25 activities in test tube experiments. In cortical neurons, however, and in vivo in Alzheimer’s disease (AD) model mice, the peptide specifically inhibits the Cdk5/p25 complex and not the endogenous Cdk5/p35. To account for the selective inhibition of Cdk5/p25 activity, we propose that the “p10” N-terminal domain of p35, absent in p25, spares Cdk5/p35 because p10 binds to macromolecules (e.g., tubulin and actin) as a membrane-bound multimeric complex that favors p35 binding to Cdk5 and catalysis. To test this hypothesis, we focused on Munc 18, a key synapse-associated neuronal protein, one of many proteins copurifying with Cdk5/p35 in membrane-bound multimeric complexes. Here we show that, in vitro, the addition of p67 protects Cdk5/p35 and has no effect on Cdk5/p25 activity in the presence of TFP5. In cortical neurons transfected with p67siRNA, we also show that TFP5 inhibits Cdk5/p35 activity, whereas in the presence of p67 the activity is protected. It does so without affecting any other kinases of the Cdk family of cyclin kinases. This difference may be of significant therapeutic value because the accumulation of the deregulated, hyperactive Cdk5/p25 complex in human brains has been implicated in pathology of AD and other neurodegenerative disorders. The American Society for Cell Biology 2016-11-01 /pmc/articles/PMC5170856/ /pubmed/27630261 http://dx.doi.org/10.1091/mbc.E15-12-0857 Text en © 2016 Amin et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Amin, Niranjana D.
Zheng, Yali
BK, Binukumar
Shukla, Varsha
Skuntz, Susan
Grant, Philip
Steiner, Joseph
Bhaskar, Manju
Pant, Harish C.
The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35
title The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35
title_full The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35
title_fullStr The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35
title_full_unstemmed The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35
title_short The interaction of Munc 18 (p67) with the p10 domain of p35 protects in vivo Cdk5/p35 activity from inhibition by TFP5, a peptide derived from p35
title_sort interaction of munc 18 (p67) with the p10 domain of p35 protects in vivo cdk5/p35 activity from inhibition by tfp5, a peptide derived from p35
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170856/
https://www.ncbi.nlm.nih.gov/pubmed/27630261
http://dx.doi.org/10.1091/mbc.E15-12-0857
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