The evolution of human SIRT1 for multi-specificity is enabled by active-site adaptation
Hendler, A.; Akiva, E.; Sandhu, M.; Goldberg, D.; Arbely, E.; Jackson, C. J.; Aharoni, A.
Show abstract
Many enzymes that catalyze protein post-translational modifications (PTM) can specifically modify multiple target proteins. However, little is known regarding the molecular basis and evolution of multi-specificity in these enzymes. Here, we used bioinformatics and experimental approaches to investigate the molecular basis and evolution of multi-specificity in the sirtuin-1 (SIRT1) deacetylase. Guided by bioinformatics analysis of SIRT1 orthologues and substrates, we identified and examined key mutations that have occurred during the evolution of human SIRT1. We found that while these mutants maintain high activity toward conserved histone substrates they exhibit a dramatic loss of activity toward acetylated p53 protein that appeared only in Metazoa. These results demonstrate that active site substitutions in SIRT1 are essential to enable the inclusion of p53 substrate. Our results are consistent with a model in which promiscuous ancestral activity can provide an evolutionary starting point from which multispecificity toward a number of cellular substrates can develop.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres 94%
- Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number 94%
- Structural basis for interaction between CLAMP and MSL2 proteins involved in the specific recruitment of the dosage compensation complex in Drosophila 94%
Similar papers in this journal
Similar papers in this journal
- The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation 95%
- Arabidopsis Nicotianamine Synthases (NAS) comprise a common core-NAS domain fused to a variable auto-inhibitory C-terminus 93%
- Lineage-specific amino acids define functional attributes of the protomer-protomer interfaces for the Rad51 and Dmc1 recombinases 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.