The role of Nα‐terminal acetylation in protein conformation

• Published in: The FEBS journal Vol. 292; no. 3; pp. 453 - 467
• Main Authors: Calis, Sam, Gevaert, Kris
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2025
• Subjects: Acetylation; Acetyltransferase; acetyltransferases; actin; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; alpha‐synuclein; Animals; Enzymes; Eukaryotes; eukaryotic cells; Folding; fused in Sarcoma; Humans; Huntingtin; Huntingtin Protein - chemistry; Huntingtin Protein - metabolism; N‐terminal acetylation; N‐terminal acetyltransferases; parvalbumin; Polypeptides; Protein Conformation; Protein Folding; Protein Processing, Post-Translational; Protein structure; Proteins; Proteomics; Synuclein; Terminal protein; tropomyosin; actin; tropomyosin; proteomics; huntingtin; parvalbumin; fused in Sarcoma; N‐terminal acetylation; alpha‐synuclein; protein folding; N‐terminal acetyltransferases
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17209

Especially in higher eukaryotes, the N termini of proteins are subject to enzymatic modifications, with the acetylation of the alpha‐amino group of nascent polypeptides being a prominent one. In recent years, the specificities and substrates of the enzymes responsible for this modification, the Nα‐terminal acetyltransferases, have been mapped in several proteomic studies. Aberrant expression of, and mutations in these enzymes were found to be associated with several human diseases, explaining the growing interest in protein Nα‐terminal acetylation. With some enzymes, such as the Nα‐terminal acetyltransferase A complex having thousands of possible substrates, researchers are now trying to decipher the functional outcome of Nα‐terminal protein acetylation. In this review, we zoom in on one possible functional consequence of Nα‐terminal protein acetylation; its effect on protein folding. Using selected examples of proteins associated with human diseases such as alpha‐synuclein and huntingtin, here, we discuss the sometimes contradictory findings of the effects of Nα‐terminal protein acetylation on protein (mis)folding and aggregation. This review explores the eukaryotic Nα‐terminal acetyltransferases (NAT), a family of key enzymes that co‐translationally modify protein N‐termini. Aberrant expression and mutant NAT variants are implicated in various human diseases such as cancer, neurodevelopmental disorders and a family of rare developmental syndromes. Highlighting the complex role of Nα‐terminal acetylation in protein folding and aggregation, here, we have reviewed its impact on disease‐associated proteins including alpha‐synuclein and huntingtin.