Overlap of NatA and IAP substrates implicates N-terminal acetylation in protein stabilization

Mueller, Franziska; Friese, Alexandra; Pathe, Claudio; da Silva, Richard Cardoso; Rodriguez, Kenny Bravo; Musacchio, Andrea und Bange, Tanja (2021): Overlap of NatA and IAP substrates implicates N-terminal acetylation in protein stabilization. In: Science Advances, Bd. 7, Nr. 3, eabc8590

Abstract

SMAC/DIABLO and HTRA2 are mitochondrial proteins whose amino-terminal sequences, known as inhibitor of apoptosis binding motifs (IBMs), bind and activate ubiquitin ligases known as inhibitor of apoptosis proteins (IAPs), unleashing a cell's apoptotic potential. IBMs comprise a four-residue, loose consensus sequence, and binding to IAPs requires an unmodified amino terminus. Closely related, IBM-like N termini are present in approximately 5% of human proteins. We show that suppression of the N-alpha-acetyltransferase NatA turns these cryptic IBM-like sequences into very efficient IAP binders in cell lysates and in vitro and ultimately triggers cellular apoptosis. Thus, amino-terminal acetylation of IBM-like motifs in NatA substrates shields them from IAPs. This previously unrecognized relationship suggests that amino-terminal acetylation is generally protective against protein degradation in human cells. It also identifies IAPs as agents of a general quality control mechanism targeting unacetylated rogues in metazoans.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2375-2548
• Sprache: Englisch