The biological functions of Naa10 - From amino-terminal acetylation to human disease

Abstract

N-terminal acetylation (NTA) is one of the most abundant protein modifications known, and the N-terminal acetyltransferase (NAT) machinery is conserved throughout all Eukarya. Over the past 50 years, the function of NTA has begun to be slowly elucidated, and this includes the modulation of protein-protein interaction, protein-stability, protein function, and protein targeting to specific cellular compartments. Many of these functions have been studied in the context of Naa10/NatA; however, we are only starting to really understand the full complexity of this picture. Roughly, about 40% of all human proteins are substrates of Naa10 and the impact of this modification has only been studied for a few of them. Besides acting as a NAT in the NatA complex, recently other functions have been linked to Naa10, including post-translational NTA, lysine acetylation, and NAT/KAT-independent functions. Also, recent publications have linked mutations in Naa10 to various diseases, emphasizing the importance of Naa10 research in humans. The recent design and synthesis of the first bisubstrate inhibitors that potently and selectively inhibit the NatA/Naa10 complex, monomeric Naa10, and hNaa50 further increases the toolset to analyze Naa10 function.

Keywords: Acetyltransferases; Amino-terminal acetylation; Enzymology; NAA10; NAA15; NAA50; Ogden syndrome; Proteins; Proteomics; ard1.

Fig. 1

The co-translational N-terminal protein modification process. As soon as the nascent polypeptide chain emerges from the ribosome exit tunnel, the initiator methionine is cleaved by methionine aminopeptidases (MetAPs) if the following amino acid is small and uncharged. For the sake of simplicity, this process is illustrated by one enzyme despite the fact that other enzymes including peptide deformylases are involved, depending on organism and cellular compartment. Subsequently, the new N-termini can get acetylated by NatA, composed of the catalytic Naa10 and the auxiliary subunit Naa15. The majority of cytosolic proteins fall into this category. If the iMet is not processed, NTA can be accomplished by NatB (composed of Naa20 and Naa25), NatC (Naa30, Naa35, Naa38), NatD (Naa40) NatE (Naa50 and possibly Naa15) and NatF (Naa60). Figure modified from Kalvik and Arnesen (2013).

Fig. 2

NAA10 transcript variants. A) Human NAA10 according to RefSeq. There are 3 human transcript variants. Variant 1 represents the longest transcript and encodes the longest isoform (235 aa). Variant 2 lacks in-frame exon 6 in the coding region and is shorter than isoform 1 (220 aa). Variant 3 uses an alternate in-frame splice site in exon 3 (229 aa). B) In mouse, two NAA10 transcripts are described. Variant 1 represents the shorter transcript but the longer isoform (235 aa). Variant 2 uses an alternate splice site (exon 8), which results in a frameshift that induces a stop codon (*). The resulting isoform has a shorter and distinct C-terminus.

Fig. 3

Multiple functions of Naa10. Associated with the ribosome in the NatA complex, Naa10 co-translationally acetylates the N^α-terminal amino group of the nascent polypeptide chains of classical substrates as they emerge from the ribosome. Naa15 as well as the signal recognition particle SRP and nascent polypeptide-associated complex NAC might bind competitively to similar regions on the ribosome near the exit tunnel (see below). This might indicate a general involvement of Naa10 in protein biogenesis. Uncomplexed Naa10 post-translationally N^α-acetylates proteins starting with acidic side chains and might also N^ε-acetylate internal lysines. Furthermore, it has been suggested that Naa10 translocates into the nucleus where it acts in cooperation with transcription factors to modulate protein expression.

Fig. 4

Possible role of Naa10 in cellular hypoxia. Under normoxic conditions, HIF1α is hydroxylated by PHD proteins on prolines, leading to the subsequent ubiquitination by pVHL and rapid proteasomal degradation of HIF1α. Furthermore, hydroxylation of Asn₉₀₃ by FIH disrupts binding of HIF1α to its transcriptional co-activators p300/CBP, and hence the transcriptional activity of the HIF-1α. Many reports have shown a direct interaction of Naa10 with HIF-1α, suggesting a link in this pathway. Naa10 might either directly or indirectly stimulate HIF1α lysine acetylation, thereby destabilizing HIF1α, possibly through promoting its interaction with pVHL and PHDs. MTA1 counteracts the action of Naa10 by recruiting HDAC1 which leads to a deacetylation and subsequent stabilization of HIF-1α.

Fig. 5

Pictures related to Ogden syndrome. Shown are pictures of individual III:4 and III:6 from family one (A) and individual II:1 and individual III:2 from family 2 (B).