NAA15 explained

N-alpha-acetyltransferase 15, NatA auxiliary subunit also known as gastric cancer antigen Ga19 (GA19), NMDA receptor-regulated protein 1 (NARG1), and Tbdn100 is a protein that in humans is encoded by the NAA15 gene.[1] NARG1 is the auxiliary subunit of the NatA (Nα-acetyltransferase A) complex. This NatA complex can associate with the ribosome and catalyzes the transfer of an acetyl group to the Nα-terminal amino group of proteins as they emerge from the exit tunnel.

Gene and transcripts

Human NAA15 is located on chromosome 4q31.1 and contains 23 exons. Initially, 2 mRNA species were identified, of size 4.6 and 5.8 kb, both harboring the same open reading frame encoding a putative protein of 866 amino acids (~105 kDa) protein that can be detected in most human adult tissues.[1] According to RefSeq/NCBI, only one human transcript variant exists, although 2 more isoforms are predicted.[2] In addition to full length Naa15, an N-terminally truncated variant of Naa15 (named tubedown-1), Naa15273-865 has been described; however, in mouse only full length Naa15 is widely expressed, whereas smaller transcripts seem to visualized only in heart and testis.[3] [4]

In addition to this, a NAA15 gene duplication, NAA16, has been identified, and the encoded protein shares 70% sequence identity to hNaa15 and is expressed in a variety of human cell lines, but is generally less abundant as compared to hNaa15.[5] Three isoforms of Naa16 are validated so far (NCBI RefSeq). Mouse NAA15 is located on chromosome 2 D and contains 20 exons, whereas mouse NAA16 is located on chromosome 14 D3 and consists of 21 exons.

In principle, NatA can assemble from all the Naa10 and Naa15 isoforms in human and mouse, creating a more complex and flexible system for Nα-terminal acetylation as compared to lower eukaryotes.[5] [6] [7]

Structure

The X-ray crystal structure of the holo-NatA complex (Naa10/Naa15) from S. pombe revealed that Naa15 is composed of 13 conserved helical bundle tetratricopeptide repeat (TPR) motifs and adopts a ring-like topology that wraps around the catalytic subunit of NatA, Naa10.[8] This interaction induces conformational changes in the catalytic center of Naa10 that allows the acetylation of conventional NatA substrates.[8] The crystal structure of human NatA bound to the protein HYPK has also been solved.[9]

Because TPR motifs mediate protein–protein interactions, it has been postulated that this domain may facilitate the interaction with other NatA-binding partners such as the ribosome and Naa50/NatE.[8] Naa15 harbors a putative NLS between residues 612-628 (KKNAEKEKQQRNQKKKK); however, analysis of the nuclear localization of Naa15 revealed discrepant results.[4] [10]

Function

Naa15, together with its catalytic subunit Naa10, constitutes the evolutionarily conserved NatA (Nα-acetyltransferase A) complex, which acetylates the α-amino group of the first amino acid residue of proteins starting with small side chains like serine, glycine, alanine, threonine and cysteine, after the initiator methionine has been cleaved by methionine aminopeptidases.[10] [11] [12] [13] [14] [15] [16]

Both Naa15 and Naa16 interact with the ribosome in yeast (via the ribosomal proteins, uL23 and uL29), humans and rat, thereby linking the NatA/Naa10 to the ribosome and facilitating co-translational acetylation of nascent polypeptide chains as they emerges from the exit tunnel.[5] [17] [18] [19] [20] [21] Furthermore, Naa15 might act as a scaffold for other factors, including the chaperone like protein HYPK (Huntingtin Interacting Protein K) and Naa50, the catalytic acetyltransferase subunit of NatE[18] [19] [22] [23] In S. cerevisiae, NAA15Δ and NAA10Δ knockout cells exhibit the same phenotype, and biochemical data indicate that uncomplexed Naa15 is unstable and gets degraded.[8] [24] [25] [26] Therefore, Naa15 function has been closely linked to the acetyltransferase activity of Naa10 as part of the NatA complex. NatA may also regulate co-translational protein folding and protein targeting to the endoplasmic reticulum, possibly through competition with SRP and NAC for the same ribosomal binding sites or through yet unknown interference with other ribosome-associated protein biogenesis factors, such as the MetAPs, the chaperones Hsp70/Hsp40, SRP and NAC, which act on newly synthesized proteins as soon as they emerge from the ribosome exit tunnel.[17] [20] [27] [28] [29] [30] [31] However, the exact mechanism of such action is obscure. Apart from this, Naa15 has been linked to many cellular processes, including the maintenance of a healthy retina,[32] [33] [34] endothelial cell permeability,[34] tumor progression,[1] [35] generation and differentiation of neurons[11] [36] [37] apoptosis[5] [38] and transcriptional regulation;[4] however, it is not well understood whether these are NatA-independent or -dependent functions of Naa15.

Disease

Two damaging de novo NAA15 mutations were reported by exome sequencing in parent-offspring trios with congenital heart disease.[39] Patient 1 harbors a frameshift mutation (p. Lys335fs) and displays heterotaxy (dextrocardia, total anomalous pulmonary venous return, left superior vena cava, hypoplastic TV, double outlet right ventricle, hypoplastic RV, D-transposition of the great arteries, pulmonic stenosis) and hydronephrosis, asplenia, malrotation and abnormal neuro-development, the second patient harbors a nonsense mutation (p.S761X) and displays conotruncal defects (tetralogy of Fallot, single left coronary artery).

Further reading

Notes and References

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  2. Pruitt KD, Tatusova T, Maglott DR . Donna R. Maglott. NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. . Nucleic Acids Research . 35 . Database issue . D61–5 . January 2007 . 17130148 . 10.1093/nar/gkl842 . 1716718.
  3. Gendron RL, Adams LC, Paradis H . Tubedown-1, a novel acetyltransferase associated with blood vessel development. . Developmental Dynamics . 218 . 2 . 300–15 . June 2000 . 10842358 . 10.1002/(sici)1097-0177(200006)218:2<300::aid-dvdy5>3.0.co;2-k. free .
  4. Willis DM, Loewy AP, Charlton-Kachigian N, Shao JS, Ornitz DM, Towler DA . Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex. . The Journal of Biological Chemistry . 277 . 40 . 37280–91 . 4 October 2002 . 12145306 . 10.1074/jbc.m206482200. free .
  5. Arnesen T, Gromyko D, Kagabo D, Betts MJ, Starheim KK, Varhaug JE, Anderson D, Lillehaug JR . A novel human NatA Nalpha-terminal acetyltransferase complex: hNaa16p-hNaa10p (hNat2-hArd1). . BMC Biochemistry . 10 . 15 . 2009 . 19480662 . 10.1186/1471-2091-10-15 . 2695478 . free .
  6. Arnesen T, Betts MJ, Pendino F, Liberles DA, Anderson D, Caro J, Kong X, Varhaug JE, Lillehaug JR . Characterization of hARD2, a processed hARD1 gene duplicate, encoding a human protein N-alpha-acetyltransferase. . BMC Biochemistry . 7 . 13 . 25 April 2006 . 16638120 . 10.1186/1471-2091-7-13 . 1475586 . free .
  7. Pang AL, Peacock S, Johnson W, Bear DH, Rennert OM, Chan WY . Cloning, characterization, and expression analysis of the novel acetyltransferase retrogene Ard1b in the mouse. . Biology of Reproduction . 81 . 2 . 302–9 . August 2009 . 19246321 . 10.1095/biolreprod.108.073221 . 2849813.
  8. Liszczak G, Goldberg JM, Foyn H, Petersson EJ, Arnesen T, Marmorstein R . Molecular basis for N-terminal acetylation by the heterodimeric NatA complex. . Nature Structural & Molecular Biology . 20 . 9 . 1098–105 . September 2013 . 23912279 . 10.1038/nsmb.2636 . 3766382.
  9. Gottlieb . Leah . Marmorstein . Ronen . Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. . Structure . 26 . 7 . 925–935.e8 . 10 May 2018 . 29754825 . 6031454 . 10.1016/j.str.2018.04.003 .
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  12. Park EC, Szostak JW . ARD1 and NAT1 proteins form a complex that has N-terminal acetyltransferase activity. . The EMBO Journal . 11 . 6 . 2087–93 . June 1992 . 1600941 . 556675. 10.1002/j.1460-2075.1992.tb05267.x .
  13. Mullen JR, Kayne PS, Moerschell RP, Tsunasawa S, Gribskov M, Colavito-Shepanski M, Grunstein M, Sherman F, Sternglanz R . Identification and characterization of genes and mutants for an N-terminal acetyltransferase from yeast. . The EMBO Journal . 8 . 7 . 2067–75 . July 1989 . 2551674 . 401092. 10.1002/j.1460-2075.1989.tb03615.x .
  14. Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, Varhaug JE, Vandekerckhove J, Lillehaug JR, Sherman F, Gevaert K . Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. . Proceedings of the National Academy of Sciences of the United States of America . 106 . 20 . 8157–62 . 19 May 2009 . 19420222 . 10.1073/pnas.0901931106 . 2688859. 2009PNAS..106.8157A . free .
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  16. Van Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T . NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation. . PLOS Genetics . 7 . 7 . e1002169 . July 2011 . 21750686 . 10.1371/journal.pgen.1002169 . 3131286 . free .
  17. Polevoda B, Brown S, Cardillo TS, Rigby S, Sherman F . Yeast N(alpha)-terminal acetyltransferases are associated with ribosomes. . Journal of Cellular Biochemistry . 103 . 2 . 492–508 . 1 February 2008 . 17541948 . 10.1002/jcb.21418. 86577051 .
  18. Gautschi M, Just S, Mun A, Ross S, Rücknagel P, Dubaquié Y, Ehrenhofer-Murray A, Rospert S . The yeast N(alpha)-acetyltransferase NatA is quantitatively anchored to the ribosome and interacts with nascent polypeptides. . Molecular and Cellular Biology . 23 . 20 . 7403–14 . October 2003 . 14517307 . 10.1128/mcb.23.20.7403-7414.2003 . 230319.
  19. Arnesen T, Starheim KK, Van Damme P, Evjenth R, Dinh H, Betts MJ, Ryningen A, Vandekerckhove J, Gevaert K, Anderson D . The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation. . Molecular and Cellular Biology . 30 . 8 . 1898–909 . April 2010 . 20154145 . 10.1128/mcb.01199-09 . 2849469.
  20. Raue U, Oellerer S, Rospert S . Association of protein biogenesis factors at the yeast ribosomal tunnel exit is affected by the translational status and nascent polypeptide sequence. . The Journal of Biological Chemistry . 282 . 11 . 7809–16 . 16 March 2007 . 17229726 . 10.1074/jbc.m611436200. free .
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