Three's a crowd – why did three N-terminal methyltransferases evolve for one job?

Abstract

N-terminal methylation of the α-amine group (Nα-methylation) is a post-translational modification (PTM) that was discovered over 40 years ago. Although it is not the most abundant of the Nα-PTMs, there are more than 300 predicted substrates of the three known mammalian Nα-methyltransferases, METTL11A and METTL11B (also known as NTMT1 and NTMT2, respectively) and METTL13. Of these ∼300 targets, the bulk are acted upon by METTL11A. Only one substrate is known to be Nα-methylated by METTL13, and METTL11B has no proven in vivo targets or predicted targets that are not also methylated by METTL11A. Given that METTL11A could clearly handle the entire substrate burden of Nα-methylation, it is unclear why three distinct Nα-methyltransferases have evolved. However, recent evidence suggests that many methyltransferases perform important biological functions outside of their catalytic activity, and the Nα-methyltransferases might be part of this emerging group. Here, we describe the distinct expression, localization and physiological roles of each Nα-methyltransferase, and compare these characteristics to other methyltransferases with non-catalytic functions, as well as to methyltransferases with both catalytic and non-catalytic functions, to give a better understanding of the global roles of these proteins. Based on these comparisons, we hypothesize that these three enzymes do not just have one common function but are actually performing three unique jobs in the cell.

Opposing regulation of the Nα-trimethylase METTL11A by its family members METTL11B and METTL13

“…Again, our findings with METTL11A and METTL13 are consistent with this pattern, in that their regulatory effects were still elicited by catalytically inactive mutants. This pattern highlights a distinct division among the METTL family of proteins, as some methyltransferases have both catalytic and noncatalytic functions like METTL3, METTL16, METTL11A, and METTL13, while others, like METTL14 and perhaps METTL11B ( 51 ), only seem to have noncatalytic functions. We suspect additional functions will be identified for methyltransferases that were previously thought to only have one defined role.…”

Unlocking the mysteries of alpha-N-terminal methylation and its diverse regulatory functions

“…When all three are present, the regulatory effects of METTL13 override those of NTMT2. These findings result in a model where these three MTases use the formation of a macromolecular complex to regulate translation by methylating eEF1α, with separate roles for each enzyme ( 113 ). eEF1α is the only substrate for METTL13, but macromolecular complex regulation involving these enzymes may extend to additional substrates.…”