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NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein.

The post-translational methylation of alpha-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L33 (refs 1, 2), but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be alpha-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of alpha-N-methylation has been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating that they may be targets of the same, unknown enzyme. The initiating Met is cleaved, and the exposed alpha-amino group is mono-, di- or trimethylated. Here we report the discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET (also known as TAF-I or PHAPII) and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.

Pubmed ID: 20668449

Authors

  • Tooley CE
  • Petkowski JJ
  • Muratore-Schroeder TL
  • Balsbaugh JL
  • Shabanowitz J
  • Sabat M
  • Minor W
  • Hunt DF
  • Macara IG

Journal

Nature

Publication Data

August 26, 2010

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM050526
  • Agency: NIGMS NIH HHS, Id: R01 GM050526-17

Mesh Terms

  • Cell Cycle Proteins
  • Cell Line
  • Chromosome Segregation
  • Gene Knockdown Techniques
  • Guanine Nucleotide Exchange Factors
  • HeLa Cells
  • Histone Chaperones
  • Humans
  • Methyltransferases
  • Models, Molecular
  • Mutation
  • Nuclear Proteins
  • Protein Binding
  • Protein Structure, Tertiary
  • Retinoblastoma Protein
  • Spindle Apparatus
  • Transcription Factors