NAC controls cotranslational N-terminal methionine excision in eukaryotes

Area of Science:

• Molecular Biology
• Protein Biochemistry
• Cellular Homeostasis

Background:

• N-terminal methionine excision is a crucial cotranslational process catalyzed by methionine aminopeptidases (METAPs).
• The precise mechanisms governing METAP interaction with ribosomes and ensuring cleavage specificity remain largely unknown.
• This process is vital for cell homeostasis and proper protein biogenesis.

Purpose of the Study:

• To elucidate the mechanism by which methionine aminopeptidases (METAPs) interact with ribosomes.
• To understand how methionine excision specificity is achieved during protein synthesis.
• To investigate the role of the nascent polypeptide-associated complex (NAC) in regulating METAP activity.

Main Methods:

• Investigated the interaction between METAP1 and the nascent polypeptide-associated complex (NAC).
• Utilized biochemical assays to study complex formation at the ribosomal tunnel exit.
• Examined the impact of NAC on methionine excision from different protein classes.

Main Results:

• Discovered that the nascent polypeptide-associated complex (NAC) governs ribosome binding of METAP1 in eukaryotes.
• NAC recruits METAP1 via a flexible tail, forming an active methionine excision complex at the ribosomal tunnel exit.
• This interaction ensures efficient methionine excision from cytosolic proteins but spares ER-targeted proteins.

Conclusions:

• NAC acts as a crucial regulator of methionine aminopeptidase (METAP) activity at the ribosome.
• A novel mechanism for controlling access of protein biogenesis factors to translating ribosomes is proposed.
• This finding sheds light on the specificity of cotranslational protein modifications.