A synopsis of eukaryotic Nα-terminal acetyltransferases: nomenclature, subunits and substrates

  • Bogdan Polevoda1,

    Affiliated with

    • Thomas Arnesen2, 3, 4 and

      Affiliated with

      • Fred Sherman1Email author

        Affiliated with

        BMC Proceedings20093(Suppl 6):S2

        DOI: 10.1186/1753-6561-3-S6-S2

        Published: 4 August 2009

        Abstract

        We have introduced a consistent nomenclature for the various subunits of the NatA-NatE N-terminal acetyltransferases from yeast, humans and other eukaryotes.

        Introduction

        N-terminal acetylation has been extensively studied in yeast and humans and represents one of the most common protein modifications in eukaryotes, occurring on approximately 57% of yeast proteins and 84% human proteins [1], although it is rare in prokaryotes. Eukaryotic proteins initiate with methionine residues, which are cleaved from nascent chains if the penultimate residue has a radius of gyration of 1.29 Å or less [2]. N-terminal acetylation subsequently occurs on certain of the proteins, either containing or lacking the methionine residue, as depicted in Fig. 1. The salient features of N-terminal acetylation are summarized in Table 1 and Fig. 2. Detailed reviews on the N-terminal acetyltransferases have appeared [37], and the N-terminal acetylation status of 742 human and 616 yeast protein N-termini have been compiled [1]. The wide range and diversity of substrates is due in part to the large number of different N-terminal acetylating enzymes, NatA-NatE. The sequence requirements for N-terminal acetylation vary with the N-terminal acetyltransferase. Only two amino acid residues, Met-Asn-, Met-Asp-, or Met-Glu-, are required for at least partial N-terminal acetylation by NatB [1, 8]. On the other hand, 30 to 50 specific amino acids are required for N-terminal acetylation by NatD [9]. Each of the three major N-terminal acetyltransferases, NatA, NatB and NatC, contain a catalytic subunit, and one or two auxiliary subunits (Table 1). The sequence and functions of the yeast and human orthologous subunits are obviously related. A yeast ard1nat1-Δ strain was phenotypically complemented by hARD1 hNAT1, suggesting that yNatA and hNatA are similar. However, heterologous combinations, hARD1 yNAT1 and yARD1 hNAT1, were not functional in yeast, suggesting significant structural subunit differences between the species [1].
        Table 1

        Revised nomenclature for N-terminal acetyltransferases

        Type

        NatA

        NatB

        NatC

        NatD

        NatE

        Original

             

           Catalytic subunit

        Ard1p

        Nat3p

        Mak3p

        Nat4p

        Nat5p

           Auxiliary subunit

        Nat1p

        Mdm20p

        Mak10p

         

           

        Mak31p

          

        Revised

             

           Catalytic subunit

        Naa10p

        Naa20p

        Naa30p

        Naa40p

        Naa50p

           Auxiliary subunit

        Naa15p

        Naa25p

        Naa35p

         

           

        Naa38p

          

        Number of yeast substrates

        ~2,000

        ~1,000

        ~250

        2?

        ?

        Substrates*

        Ser-

        Met-Glu-

        Met-Ile-

        Ser-Gly-etc-

        ?

         

        Ala-

        Met-Asp-

        Met-Leu-

          
         

        Gly-

        Met-Asn-

        Met-Trp-

          
         

        Thr-

         

        Met-Phe-

          
         

        Val-‡

            
         

        Cys-¶

            
         

        ------------2 to 8 amino acids-----------

        30–50 a. a

        ?

        Naa50p is inferred to be an N-terminal acetyltransferase because of its sequence homology to known NATs.

        * Acetylation occurs at least partially on all proteins with Met-Glu-, Met-Asp- and Met-Asn- termini, but only on subclasses of proteins with the other termini.

        † Naa15p may be an auxiliary subunit of NatE, as well as an auxiliary subunit of NatA.

        ‡ Found in humans but not yeast (see Figure 2 legend).

        ¶One example found in yeast (see Figure 2 legend).

        http://static-content.springer.com/image/art%3A10.1186%2F1753-6561-3-S6-S2/MediaObjects/12919_2009_Article_2743_Fig1_HTML.jpg
        Figure 1

        A summary of the major pathways of N -terminal processing in eukaryotes, showing the four different termini. 1: Uncleaved and unacetylated Met-Xxx- N-termini; 2: Cleaved and unacetylated Xxx-N-termini; 3: Uncleaved and NatB/NatC acetylated Ac-Met-Xxx- N-termini; 4: Cleaved and NatA acetylated Ac-Xxx-N-termini. See Table 1 and Figure 2 for more detail.

        http://static-content.springer.com/image/art%3A10.1186%2F1753-6561-3-S6-S2/MediaObjects/12919_2009_Article_2743_Fig2_HTML.jpg
        Figure 2

        The major pathways of N -terminal processing in eukaryotes. Two methionine aminopeptidases (MAP), Map1p and Map2p, cleave N-terminal methionine residues that have small side chains (glycine, alanine, serine, cysteine, threonine, proline, and valine), although methionine is retained on some proteins having penultimate residues of valine. Subsequently, NatA, NatB, and NatC acetylate specific sequences as shown in the figure and in Table 1. Acetylation occurs at least partially on all proteins with Met-Glu-, Met-Asp- and Met-Asn- termini, but only on subclasses of proteins with the other termini. For example, acetylation occurs at least partially on 43% of proteins in yeast and on 96% of proteins in humans with Ala- termini. In addition, Ac-Cys-, Ac-Val-, Ac-Met-Met-, and Ac-Met-Lys- termini occurs on some proteins from humans but not from yeast; it is unknown which NATs are responsible for Ac-Cys-, Ac-Met-Met-, and Ac-Met-Lys- acetylations.

        Nomenclature

        During a recent international meeting on N-terminal acetylation, it was pointed out that there is critical need to revise the gene symbols encoding the N-terminal acetyltransferases. The main reason for changing the nomenclature is so that each of the orthologous genes from different species would have the same name. Furthermore, orthologous genes were assigned not only by similarity of their sequences, but also by their action on the same set of proteins. Yeast NatA and human NatA were shown to acetylate the same set proteins by comparing a normal yeast strain with the mutant naa10naa15-ΔhNAA10 hNAA15 [1].

        The use of the different symbols NAT, ARD, MDM, and MAK is confusing, and does not provide useful information, especially when applied to human NATs. We believe it can be misleading to assign a gene symbol based on one phenotype of a mutant when a large number of proteins are affected, and when the mutant is pleiotropic.

        Most importantly, different orthologous genes should have different names. The symbols NAT1, NAT2 and NAT3 denote human genes encoding arylamine N-acetyltransferases, which are distinct from N-terminal acetyltransferases [10]. On the other hand, NCBI has designated the human homologue of the yeast NAT genes as follows: yNAT1 designated as hNARG1; yNAT3 designated as hNAT5; and yNAT5 designated as hNAT13. Also, ARD1 is used to describe the ADP-ribosylation factor domain protein 1 [11].

        Therefore, in this paper we have introduced a new nomenclature for protein N-terminal acetyltransferases in eukaryotes (Table 1). It is important to note that NAA (Nα acetyltransferases) is not used to designate any other gene in yeast or higher eukaryotes. We have assigned each of the subunits of the NatA-NatE complexes a Naa symbol, as presented in Table 1. We have also recommended a nomenclature for paralogs of human NatA complexes containing either Naa10p or Naa11p in combination with either Naa15p or Naa16p (Table 2). The revised symbols, along with synonyms from yeast and humans, are presented in Table 3. Clearly, this revised nomenclature will greatly diminish the confusion in describing orthologous subunits from different species.
        Table 2

        Paralogs

        Subunit

        Complex

        Catalytic subunit Naa10p, Naa11p

         
         

        NatA(10+15); NatA(10+16); NatA(11+15); NatA(11+16)

        Auxiliary subunit Naa15p, Naa16p

         

        Almost all human NAT subunit genes encode alternative splicing isoforms whose functions are in question, and are not considered here.

        Table 3

        Synonyms

          

        Accession no.

         

        Primary name

        Synonyms

        Yeast

        Human

        References

        Naa10p

        Ard1p; TE2

        P07347

        P41227

        [1214]

        Naa11p

        Ard2p

        -

        Q9BSU3

        [15]

        Naa15p

        Nat1p; NARG1; NATH; TBDN

        P12945

        Q9BXJ9

        [1620]

        Naa16p

        Nat2p; NARG1L

        -

        Q6N069

        [20, 21]

        Naa20p

        Nat3p; hNat5p

        Q06504

        P61599

        [8, 22, 23]

        Naa25p

        Mdm20p; p120

        Q12387

        Q14CX7

        [8, 23]

        Naa30p

        Mak3p; hNat12p

        Q03503

        Q147X3

        [2426]

        Naa35p

        Mak10p; hEGAP

        Q02197

        Q5VZE5

        [24, 25, 27]

        Naa38p

        Mak31p; hLsm8p

        P23059

        O95777

        [24, 25, 27]

        Naa40p

        Nat4p; hNat11p

        Q04751

        Q86UY6

        [28]

        Naa50p

        Nat5p; hNat13p; San

        Q08689

        Q9GZZ1

        [2931]

        An example of standard symbols: Protein, Naa10p; Gene, NAA10; Deleted gene, naa10-Δ. hNaa10p, human; yNaa10p, yeast (S. cerevisiae); mNaa10p, mouse.

        Declarations

        Acknowledgements

        This work was supported by the Norwegian Health region West (to T.A.), the Norwegian Research Council (to T.A), and the National Institutes of Health Grant R01 GM12702 (to F.S.).

        This article has been published as part of BMC Proceedings Volume 3 Supplement 6, 2009: Proceedings of the 2007 and 2008 Symposia on Protein N-terminal Acetylation. The full contents of the supplement are available online at http://​www.​biomedcentral.​com/​1753-6561/​3?​issue=​S6

        Authors’ Affiliations

        (1)
        Department of Biochemistry and Biophysics, University of Rochester Medical Center
        (2)
        Department of Molecular Biology, University of Bergen
        (3)
        Department of Surgical Sciences, University of Bergen
        (4)
        Department of Surgery, Haukeland University Hospital

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        This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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