期刊
STRUCTURE
卷 23, 期 2, 页码 332-341出版社
CELL PRESS
DOI: 10.1016/j.str.2014.10.025
关键词
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资金
- NIH [R01 GM060293, T32 GM071339]
- Proteomics core facility at the Wistar Institute (NIH) [P30 CA010815]
- University of Pennsylvania DNA Sequencing Facility at the Perelman School of Medicine, University of Pennsylvania (NIH) [P30 CA016520]
N-terminal acetylation is among the most common protein modifications in eukaryotes and is mediated by evolutionarily conserved N-terminal acetyltransferases (NATs). NatD is among the most selective NATs; its only known substrates are histones H4 and H2A, containing the N-terminal sequence SGRGK in humans. Here we characterize the molecular basis for substrate-specific acetylation by NatD by reporting its crystal structure bound to cognate substrates and performing related biochemical studies. A novel N-terminal segment wraps around the catalytic core domain to make stabilizing interactions, and the alpha 1-alpha 2 and beta 6-beta 7 loops adopt novel conformations to properly orient the histone N termini in the binding site. Ser1 and Arg3 of the histone make extensive contacts to highly conserved NatD residues in the substrate binding pocket, and flanking glycine residues also appear to contribute to substrate-specific binding by NatD, together defining a Ser-Gly-Arg-Gly recognition sequence. These studies have implications for understanding substrate-specific acetylation by NAT enzymes.
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