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

Christine E. Schaner Tooley, Janusz J. Petkowski, Tara L. Muratore-Schroeder, Jeremy L. Balsbaugh, Jeffrey Shabanowitz, Michal Sabat, Wladek Minor, Donald F. Hunt, Ian G. MacAra

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82 Scopus citations

Abstract

The post-translational methylation of α-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 α-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of α-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 α-amino group is mono-, di-or trimethylated. Here we report the discovery of the first α-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 α-N-methylation for normal bipolar spindle formation and chromosome segregation.

Original languageEnglish
Pages (from-to)1125-1128
Number of pages4
JournalNature
Volume466
Issue number7310
DOIs
StatePublished - 26 Aug 2010
Externally publishedYes

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