NAC serves as a control hub for N-terminal methionine removal on the ribosome

The N-terminal methionine is cleaved off from most cytosolic proteins whereas membrane and secreted proteins retain it. This is despite nearly half of proteins in human cells would be sequence-wise targets of the methionine aminopeptidases (MetAPs) 1 and 2, which cannot discriminate cytosolic from membrane and secreted proteins.

Based on a combination of cryo-EM, biochemical and in vivo experiments in C. elegans, the researchers discovered that NAC recruits MetAP1 via a long flexible protein tail, and that MetAP1 requires specific interactions with the globular domain of NAC and the ribosome to cleave off the N-terminal methionine. Since the heterodimeric NAC adopts this conformation when ribosomes are synthesizing cytosolic proteins, and another when the ribosome is synthesizing membrane or secreted proteins, the observed interactions rationalize how NAC selects MetAP1 substrates. Interestingly, the two flexible protein tails of NAC can simultaneously interact with MetAP1 and with SRP, which allows handover of the newly synthesized protein to either MetAP1 for processing or to SRP for targeting to the endoplasmic reticulum, depending on its sequence.

NAC, therefore, acts as a control hub at the ribosomal exit tunnel, keeping MetAP1 and the SRP in the tunnel's proximity through interactions with two flexible protein tails. The conformation of the globular NAC domain then determines which factor will act on a given nascent chain. Open questions are how MetAP2 is prevented from acting on nascent chains of membrane and ER proteins and if the discovered mechanism, with NAC as a control hub, also regulates the activity of other factors acting on nascent chains.

Link to the paper in external page "Science".