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Review
. 2021 Jan;46(1):15-27.
doi: 10.1016/j.tibs.2020.08.005. Epub 2020 Sep 8.

Protein N-Terminal Acetylation: Structural Basis, Mechanism, Versatility, and Regulation

Sunbin Deng  1 , Ronen Marmorstein  2
Affiliations
Review

Protein N-Terminal Acetylation: Structural Basis, Mechanism, Versatility, and Regulation

Sunbin Deng et al. Trends Biochem Sci. 2021 Jan.

Abstract

N-terminal acetylation (NTA) is one of the most widespread protein modifications, which occurs on most eukaryotic proteins, but is significantly less common on bacterial and archaea proteins. This modification is carried out by a family of enzymes called N-terminal acetyltransferases (NATs). To date, 12 NATs have been identified, harboring different composition, substrate specificity, and in some cases, modes of regulation. Recent structural and biochemical analysis of NAT proteins allows for a comparison of their molecular mechanisms and modes of regulation, which are described here. Although sharing an evolutionarily conserved fold and related catalytic mechanism, each catalytic subunit uses unique elements to mediate substrate-specific activity, and use NAT-type specific auxiliary and regulatory subunits, for their cellular functions.

Keywords: HYPK; IP(6); N-terminal acetylation; NATs; co-translational modification; enzyme mechanism; post-translational modification; ribosome.

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Figures

Figure 1.
Figure 1.
NAT catalytic domains share common topology and related catalytic mechanism. (A) The general topology of NAT catalytic subunits is depicted as in 2D cartoon on the left and 3D on the right panel with secondary structures shown. NATs usually contain seven β strands and four helices, but additional secondary structural elements within this topology and at their N-, C- termini are sometimes present. The α1- α2 and β6-β7 substrate binding loops are highlighted in yellow. The length of α helices and β strands does not accurately reflect actual scale in the 2D representation. The transparent magenta dots and spheres represent in the 3D representation represent the peptide and acetyl-CoA substrates, respectively. The 3D representation was generated using human NAA50 PDB: 3TFY (B) General catalytic mechanism of NATs, which transfer an acetyl group from acetyl-CoA to protein Nt-amino group is depicted. The acetyl and Nt-amino groups are colored as blue and red, respectively. A general base (or two, sometimes through a coordinated water molecule) is utilized to deprotonate the protein Nt-amino group, which subsequently attacks the acetyl group to form a tetrahedral intermediate. The deprotonated CoA is then deprotonated by a general acid (not shown) and released as the tetrahedral intermediate collapses. (C) The chemical structural of a CoA-peptide conjugate Bi-substrate analogue is shown. A linker (acetaldehyde group) is used to covalently link the CoA and peptide substrate.
Figure 2.
Figure 2.
Some NATs function independently, either in monomeric or homodimer form. (A) Structures of monomeric StRimI (PDB: 2CNM), SsNAT (PDB: 4LX9), uncomplexed SpNAA10 (PDB: 4KVX), hNAA50 (PDB: 3TFY), hNAA40 (PDB: 4U9W), and DmNAA80 (PDB: 5WJE) are shown in cartoon and color in cyan. The α1- α2 and β6-β7 substrate binding loops are highlighted in yellow. Substrate in the structures are shown in stick and colored in magenta. The hNAA40-specific N terminal domain is highlighted in grey. (B) Dimeric RimL (PDB:1S7N) and hNAA60 (PDB: 5ICW) are shown. The α1- α2 and β6-β7 substrate binding loops are highlighted in yellow. Substrate in the structures are shown in stick and colored in magenta. To form a dimer, StRimL utilizes the two β6 strands from each subunit, while hNAA60 uses the extended β6- β7 loops. The NAA60-specific N terminal domain is highlighted in grey. NAT catalytic subunits that have not been shown to function independently are not shown.
Figure 3.
Figure 3.
NATs use related but distinct mechanism to recognize their peptide substrate N-termini. Peptide binding sites of StRimI (PDB: 2CNM), complexed SpNAA10 (PDB: 4KVM, with SpNAA15 hidden), CaNAA20(PDB: 5K04, with CaNAA25 hidden), hNAA40 (PDB: 4U9W), hNAA60 (PDB: 5ICV), and DmNAA80 (PDB: 5WJE) are shown in cartoon. Peptide substrates are shown in magenta sticks. The residues labeled with a * symbol are proposed catalytic residues. Dashed lines indicate h-bonds formed between atoms. The α1- α2 and β6-β7 substrate binding loops are highlighted in yellow. Water-mediate interactions in the PDB structures are not shown.
Figure 4.
Figure 4.
Some NATs function by forming complexes with auxiliary subunits or regulatory proteins. (A) Structures of SpNatA (PDB:4KVM), CaNatB (PDB:5K04), ScNatE (PDB: 6O07) and hNAA80-actin-profilin complexes (PDB:6NBE) are shown in cartoon. (B) In humans, the dynamics and interplay between hNatA, hNAA50 and HYPK are shown. hNAA10 can exist independently. Two subunits and Inositol hexaphosphate (IP6) form hNatA (PDB: 6C9M) complex. HYPK and hNAA50 each can associate with hNatA to form competing complexes (hNatA/HYPK PDB: 6C95, hNatE PDB:6PPL). Tetrameric complex hNatE/HYPK (PDB: 6PW9) can be formed when both HYPK and hNAA50 are bound to hNatA. hNAA10, HYPK, hNAA50, hNAA15 are shown in chartreuse, salmon, teal and grey, respectively. (C) Structure of ScNatE bound to ribosome (PDB: 6HD7) is shown. Two rRNA expansion segments ES27a and ES7a are contacting NAA15 and NAA50, respectively. Two electropositive regions ERP1(N terminus of NAA15) and EPR2 (internal basic helix) on NAA15 which directly contact ribosome are shown in the zoom-in view.
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