Daumke Lab
Structural Biology of Membrane-Associated Processes
Molecular basis of protein acetylation
N-terminal acetylation is a co-translational modification known to modify protein stability and interaction. Lysine acetylation regulates protein-protein and protein-DNA interactions. Importantly, both modifications have been implied in regulating the function of peripheral membrane proteins. While N-terminal acetylation of the small GTPase ArfRP1 by the NatC complex has been shown to regulate its Golgi recruitment, lysine acetylations may affect protein-membrane interactions.
To characterize the molecular basis for these activities, we determined the crystal structure of the yeast heterotrimeric NatC complex, which exhibits a strikingly different architecture compared to previously described N-terminal acetyltransferases (NATs) (Grunwald et al., Nat Commun, 2020). Cofactor and ligand-bound structures revealed the molecular basis of how the first four amino acids of cognate substrates are recognized at an interface between two subunits. A sequence-specific, ligand-induced conformational change enables efficient acetylation. Based on detailed structure-function studies, we suggested a catalytic mechanism and identified a ribosome-binding patch in an elongated tip region of NatC. Our study reveals how NATs have divergently evolved to N-terminally acetylate specific subsets of target proteins.
In a collaborative study with the group of Ralf Langen/USC, we characterized the function of lysine acetylation in dynamin-like EHD2 and found reduced membrane-binding and remodeling in an acetylated EHD2 variant (Okada et al., Nat Commun, 2021). In a systematic fashion, the Langen group then characterized lysine acetylations in a range of membrane-remodeling proteins. These data suggested that lysine acetylation is a widespread mechanism for regulating membrane interactions in peripheral membrane-binding proteins.
Publications
- Grunwald, S., Hopf, L.V.M., Bock-Bierbaum, T., Lally, C.C.M., Spahn, C.M.T., and Daumke, O. (2020). Divergent architecture of the heterotrimeric NatC complex explains N-terminal acetylation of cognate substrates. Nat Commun 11, 5506. https://doi.org/10.1038/s41467-020-19321-8.
- Okada, A.K., Teranishi, K., Ambroso, M.R., Isas, J.M., Vazquez-Sarandeses, E., Lee, J.Y., Melo, A.A., Pandey, P., Merken, D., Berndt, L., et al. (2021). Lysine acetylation regulates the interaction between proteins and membranes. Nat Commun 12, 6466. https://doi.org/10.1038/s41467-021-26657-2.
Researchers in my group
Elena Vazquez Sarandeses (Doctoral student)
Stephan Grunwald (Doctoral student 2014 – 2019)
Main collaborations
Ralf Langen, University of Southern California.