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Protein arginine methyltransferase 1: Positively charged residues in substrate peptides distal to the site of methylation are important for substrate binding and catalysis

Academic Article
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Overview

authors

  • Osborne, T. C.
  • Obianyo, O.
  • Zhang, X.
  • Cheng, X.
  • Thompson, Paul

publication date

  • November 2007

journal

  • Biochemistry  Journal

abstract

  • Protein arginine methyltransferases (PRMTs) are a group of eukaryotic enzymes that catalyze the methylation of Arg residues in a variety of proteins (e.g., histones H3 and H4), and their activities influence a wide range of cellular processes, including cell growth, RNA splicing, differentiation, and transcriptional regulation. Dysregulation of these enzymes has been linked to heart disease and cancer, suggesting this enzyme family as a novel therapeutic target. To aid the development of PRMT inhibitors, we characterized the substrate specificity of both the rat and human PRMT1 orthologues using histone based peptide substrates. N- and C-terminal truncations to identify a minimal peptide substrate indicate that long-range interactions between enzyme and substrate are important for high rates of substrate capture. The importance of these long-range interactions to substrate capture were confirmed by "mutagenesis" experiments on a minimal peptide substrate. Inhibition studies on S-adenosyl-homocysteine, thioadenosine, methylthioadenosine, homocysteine, and sinefungin suggest that potent and selective bisubstrate analogue inhibitor(s) for PRMT1 can be developed by linking a histone based peptide substrate to homocysteine or sinefungin. Additionally, we present evidence that PRMT1 utilizes a partially processive mechanism to dimethylate its substrates.

subject areas

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Catalysis
  • Enzyme Inhibitors
  • Histones
  • Humans
  • Kinetics
  • Mass Spectrometry
  • Methylation
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides
  • Protein-Arginine N-Methyltransferases
  • Rats
  • Recombinant Proteins
  • Repressor Proteins
  • Substrate Specificity
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Identity

PubMed Central ID

  • PMC2723811

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi701558t

PubMed ID

  • 17960915
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Additional Document Info

start page

  • 13370

end page

  • 13381

volume

  • 46

issue

  • 46

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