Overlap of NatA and IAP substrates implicates N-terminal acetylation in protein stabilization
Open Access
- 15 January 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 7 (3), eabc8590
- https://doi.org/10.1126/sciadv.abc8590
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.Funding Information
- European Research Council
- Deutsche Forschungsgemeinschaft
This publication has 75 references indexed in Scilit:
- N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatBProceedings of the National Academy of Sciences, 2012
- Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-α-Acetylation FeaturesMolecular & Cellular Proteomics, 2012
- Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesisProceedings of the National Academy of Sciences, 2012
- Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell SurvivalCell, 2011
- Proteome-derived Peptide Libraries Allow Detailed Analysis of the Substrate Specificities of Nα-acetyltransferases and Point to hNaa10p as the Post-translational Actin Nα-acetyltransferaseMolecular & Cellular Proteomics, 2011
- The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27The EMBO Journal, 2010
- Protein N-Terminal Processing: Substrate Specificity of Escherichia coli and Human Methionine AminopeptidasesBiochemistry, 2010
- Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humansProceedings of the National Academy of Sciences, 2009
- MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantificationNature Biotechnology, 2008
- A genome-wide RNAi screen reveals multiple regulators of caspase activationThe Journal of cell biology, 2007