Analysis of the inhibitory elements in the p5 peptide fragment of the CDK5 activator, p35, CDKR1 protein

B. K. Binukumar, Varsha Shukla, Niranjana D. Amin, Manju Bhaskar, Suzanne Skuntz, Joseph Steiner, Dirk Winkler, Steven L. Pelech, Harish C. Pant

Research output: Contribution to journalArticlepeer-review

Abstract

Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles, it is well documented that cyclindependent kinase 5 (CDK5), a critical neuronal protein kinase in nervous system development, function, and survival, when deregulated and hyperactivated induces Alzheimer's disease (AD) and amyotrophic lateral sclerosis and Parkinson's disease-like phenotypes in mice. In a recent study, we demonstrated that p5, a small, truncated fragment of 24 amino acid residues derived from the CDK5 activator protein 35 (NCK5A, p35), selectively inhibited deregulated CDK5 hyperactivity and ameliorated AD phenotypes in model mice. In this study, we identified the most inhibitory elements in the p5 peptide fragment. Each amino acid residue in p5was systematically replaced with its homologous residues that may still be able to functionally substitute. The effects of these p5 peptide analogs were studied on the phosphotransferase activities of CDK5/p35, CDK5/p25, ERK1, and GSK3β. The mimetic p5 peptide (A/V substitution at the C-terminus of the peptide) in the sequence, KNAFYERALSIINLMTSKMVQINV (p5-MT) was the most effective inhibitor of CDK5 kinase activity of 79 tested mimetic peptides including the original p5 peptide, KEAFWDRCLSVINLMSSKMLQINA (p5-WT). Replacement of the residues in C-terminus end of the peptide affected CDK5 phosphotransferase activity most significantly. These peptides were strong inhibitors of CDK5, but not the related proline-directed kinases, ERK1 and GSK3β.

Original languageEnglish (US)
Pages (from-to)1009-1017
Number of pages9
JournalJournal of Alzheimer's Disease
Volume48
Issue number4
DOIs
StatePublished - Oct 27 2015

Keywords

  • Alzheimer's disease
  • CDK5 activator protein 35
  • cyclin-dependent kinase 5
  • phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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