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

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Little is known about the function of α-N methylation, an unusual post-translational modification in which the amino-terminal residues of proteins are methylated. One known example is that α-N methylation of the Ran guanine nucleotide-exchange factor RCC1 is required for its association with chromatin. More than 30 years ago, it was suggested that a eukaryotic α-N-specific methyltransferase might exist, and now one has been found in HeLa cells. Schaner et al. describe the first known α-N-methyltransferase, named N-terminal RCC1 methyltransferase (NRMT). They identify the NRMT recognition sequence and several new methylation targets, including the tumour suppressor proteins SET and retinoblastoma protein (Rb). A requirement for α-N-methylation is also shown in normal bipolar spindle formation and chromosome segregation. α-N-methylation is an unusual post-translational modification in which the amino-terminal residues of proteins are methylated. One example is the Ran guanine nucleotide-exchange factor, RCC1, which requires methylation for its association with chromatin. These authors describe the first α-N-methyltransferase, named N-terminal RCC1 methyltransferase (NRMT). They identify the NRMT recognition sequence and several new methylation targets, and demonstrate the importance of α-N-methylation for normal bipolar spindle formation and chromosome segregation. 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-methylated3,4,5,6,7,8,9,10. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of α-N-methylation has been identified3,11. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects3,11, 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 enzyme3,12. 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 mutants3, demonstrating the importance of α-N-methylation for normal bipolar spindle formation and chromosome segregation.

This publication has 32 references indexed in Scilit: