Substrate-induced control of product formation by protein arginine methyltransferase 1

Biochemistry. 2013 Jan 8;52(1):199-209. doi: 10.1021/bi301283t. Epub 2012 Dec 21.

Abstract

Protein arginine methyltransferases (PRMTs) aid in the regulation of many biological processes. Accurate control of PRMT activity includes recognition of specific arginyl groups within targeted proteins and the generation of the correct level of methylation, none of which are fully understood. The predominant PRMT in vivo, PRMT1, has wide substrate specificity and is capable of both mono- and dimethylation, which can induce distinct biological outputs. What regulates the specific methylation pattern of PRMT1 in vivo is unclear. We report that PRMT1 methylates a multisite peptide substrate in a nonstochastic manner, with less C-terminal preference, consistent with the methylation patterns observed in vivo. With a single targeted arginine, PRMT1 catalyzed the dimethylation in a semiprocessive manner. The degree of processivity is regulated by substrate sequences. Our results identify a novel substrate-induced mechanism for modulating PRMT1 product specificity. Considering the numerous physiological PRMT1 substrates, as well as the distinct biological outputs of mono- and dimethylation products, such fine-tuned regulation would significantly contribute to the accurate product specificity of PRMT1 in vivo and the proper transmission of biochemical information.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arginine / chemistry
  • Arginine / metabolism*
  • Methylation
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Peptides / metabolism*
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Rats
  • Substrate Specificity

Substances

  • Peptides
  • polyarginine
  • Arginine
  • PRMT1 protein, rat
  • Protein-Arginine N-Methyltransferases