Acetylation refers to the process of introducing an acetyl group (resulting in an acetoxy group) into a compound, namely the substitution of an acetyl group for an active hydrogen atom. A reaction involving the replacement of the hydrogen atom of a hydroxyl group with an acetyl group (CH3 CO) yields a specific ester, the acetate. Acetic anhydride is commonly used as an acetylating agent reacting with free hydroxyl groups. For example, it is used in the synthesis of aspirin and heroin.
Protein acetylation 1
N-terminal acetylation 1.1
N-terminal acetyltransferases 1.1.1
- NatA 220.127.116.11
- NatB 18.104.22.168
- NatC 22.214.171.124
- NatD 126.96.36.199
- NatE 188.8.131.52
- NatF 184.108.40.206
N-terminal acetylation function 1.1.2
- Protein stability 220.127.116.11
- Protein localization 18.104.22.168
- Metabolism and apoptosis 22.214.171.124
- Protein synthesis 126.96.36.199
- Cancer 1.1.3
- N-terminal acetyltransferases 1.1.1
Lysine acetylation and deacetylation 1.2
- Acetylation of p53 188.8.131.52
- Implications for cancer therapy 184.108.40.206
- Acetylation of tubulin 220.127.116.11
- Implications for cancer therapy 18.104.22.168
- Acetylation of STAT3 22.214.171.124
- Therapeutic implications for cancer therapy 126.96.36.199
- p53 1.2.1
- N-terminal acetylation 1.1
- Acetylation of wood 2
- See also 3
- References 4
Acetylation is an important modification of proteins in cell biology; and proteomics studies have identified thousands of acetylated mammalian proteins. Protein modification consists of co-translational modification and post-translational modification. Co-translational modification is the process of covalently altering one or more amino acids in a protein at the same time as its mRNA is being translated on polyribosomes; and post-translational modification includes protein phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, acetylation, lipidation and proteolysis before becoming the mature protein product. Acetylation occurs as a co-translational and post-translational modification of proteins, for example, histones, p53, and tubulins. Among these proteins, chromatin proteins and metabolic enzymes are highly represented, indicating that acetylation has a considerable impact on gene expression and metabolism. In bacteria, 90% of proteins involved in central metabolism of Salmonella enteric are acetylated.
N-terminal acetylation is one of the most common co-translational covalent modifications of proteins in eukaryotes, and it is crucial for the regulation and function of different proteins. N-terminal acetylation plays an important role in the synthesis, stability and localization of proteins. And about 85% of all human proteins and 68% in yeast are acetylated at their Nα-terminus. Several proteins from prokaryotes and archaea are also modified by N-terminal acetylation.
N-terminal Acetylation is catalyzed by a set of enzyme complexes, the N-terminal acetyltransferases (NATs). NATs transfer an acetyl group from acetyl-coenzyme A (Ac-CoA) to the α-amino group of the first amino acid residue of the protein. Different NATs are responsible for the acetylation of nascent protein N-termini, and the acetylation was found to be irreversible so far.
To date, six different NATs have been found in humans - NatA, NatB, NatC, NatD, NatE and NatF. Each of these different enzyme complexes is specific for different amino acids or amino acid sequences which is shown in the following table.Table 1. The Composition and Substrate specificity of NATs.
|NAT||Subunits (catalytic subunits are in bold.)||Substrates|
|NatA||Naa10 (Ard1) Naa15 (Nat1)||Ser-, Ala-, Gly-, Thr-, Val-, Cys- N-termini|
|NatB||Naa20 (Nat3) Naa25 (Mdm20)||Met-Glu-, Met-Asp-, Met-Asn-, Met-Gln- N-termini|
|NatC||Naa30 (Mak3) Naa35 (Mak10) Naa40 (Nat5)||Met-Leu-, Met-Ile-, Met-Trp-, Met-Phe- N-termini|
|NatD||Naa40 (Nat4)||Ser-Gly-Gly-, Ser-Gly-Arg- N-termini|
|NatE||Naa50 (Nat5) Naa10 (Ard1) Naa15 (Nat1)||Met-Leu-, Met-Ala-, Met-Lys-, Met-Met- N-termini|
|NatF||Naa60||Met-Lys-, Met-Leu-, Met-Ile-, Met-Trp-, Met-Phe- N-termini|
NatA is composed of two subunits, the catalytic subunit Naa10 and the auxiliary subunit Naa15. NatA subunits are more complex in higher eukaryotes than in lower eukaryotes. In addition to the genes NAA10 and NAA15, the mammal-specific genes NAA11 and NAA16, make functional gene products, which form different active NatA complexes. Four possible hNatA catalytic-auxiliary dimers are formed by these four proteins. However, Naa10/Naa15 is the most abundant NatA.
NatA acetylates Ser, Ala-, Gly-, Thr-, Val- and Cys N-termini after the initiator methionine is removed by methionine amino-peptidases. These amino acids are more frequently expressed in the N-terminal of proteins in eukaryotes, so NatA is the major NAT corresponding to the whole number of its potential substrates.
Several different interaction partners are involved in the N-terminal acetylation by NatA. Huntingtin interacting protein K (HYPK) interacts with hNatA on the ribosome to affect the N-terminal acetylation of a subset of NatA substrates. Subunits hNaa10 and hNaa15 will increase the tendency for aggregation of Huntingtin if HYPK is depleted. Hypoxia-inducible factor (HIF)-1α has also been found to interact with hNaa10 to inhibit hNaa10-mediated activation of β-catenin transcriptional activity.
NatB complexes are composed with the catalytic subunit Naa20p and the auxiliary subunit Naa25p, which are both found in yeast and humans. In yeast, all the NatB subunits are ribosome-associated; but in humans, NatB subunits are both found to be ribosome-associated and non-ribosomal form. NatB acetylates the N-terminal methionine of substrates starting with Met-Glu-, Met-Asp-, Met-Asn- or Met-Gln- N termini.
NatC complex consists of one catalytic subunit Naa30p and two auxiliary subunits Naa35p and Naa38p. All three subunits are found on the ribosome in yeast, but they are also found in non-ribosomal NAT forms like Nat2. NatC complex acetylates the N-terminal methionine of substrates Met-Leu-, Met-Ile-, Met-Trp- or Met-Phe N-termini.
NatD is only composed with the catalytic unit Naa40p and Naa40p and it is conceptually different form the other NATs. At first, only two substrates, H2A and H4 have been identified in yeast and humans. Secondly, the substrate specificity of Naa40p lies within the first 30-50 residues which are quite larger than the substrate specificity of other NATs. The acetylation of histones by NatD is partially associate with ribosomes and the amino acids substrates are the very N-terminal residues, which makes it different from lysine N-acetyltransferases (KATs).
NatE complex consists with subunit Naa50p and two NatA subunits, Naa10p and Naa15p. The N terminus of Naa50p substrates is different from those acetylated by the NatA activity of Naa10p.
NatF is a newly identified NAT in 2011, which is composed with Naa60p enzyme. Till now, NatF is only found in higher eukaryotes, but not in lower eukaryotes. Compared to yeast, NatF contributes to the higher abundance of N-terminal acetylation in humans. NatF complex acetylates the N-terminal methionine of substrates Met-Lys-, Met-Leu-, Met-Ile-, Met-Trp- and Met-Phe N termini which are partly overlapping with NatC and NatE.
N-terminal acetylation function
N-terminal acetylation of proteins can affect protein stability but the results and mechanism is not very clear till now. It was believed that N-terminal acetylation protects proteins from being degraded as Nα-acetylation N-termini were supposed to block N-terminal ubiquitination and subsequent protein degradation. But several studies have shown that the N-terminal acetylated protein have a similar degradation rate as proteins with a non-blocked N-terminus.
N-terminal acetylation has been shown that it can steer the localization of proteins. Arl3p contains a
- Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009). "Lysine acetylation targets protein complexes and co-regulates major cellular functions". Science 325 (5942): 834–840.
- Fritz KS, Galligan JJ, Hirschey MD, Verdin E, Petersen DR (2012). "Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice". J. Proteome Res. 11 (3): 1633–1643.
- Brook, Tom. "Protein Acetylation: Much More than Histone Acetylation". Cayman Chemical.
- Heal WP, Wickramasinghe SR, Bowyer PW, Holder AA, Smith DF, Leatherbarrow RJ, Tate EW (2008). "Site-specific N-terminal labelling of proteins in vitro and in vivo using N-myristoyl transferase and bioorthogonal ligation chemistry". Chem. Commun. (Camb.) (4): 480.
- Robert K. Murray; et al. (2003). Harper's illustrated biochemistry (26th ed.). New York ; London: McGraw-Hill.
- Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL (2010). "Regulation of cellular metabolism by protein lysine acetylation". Science 327 (5968): 1000–1004.
- Van Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T (2011). "NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation". PLoS Genet. 7 (7): e1002169.
- Starheim KK, Gevaert K, Arnesen T (2012). "Protein N-terminal acetyltransferases: when the start matters". Trends Biochem. Sci. 37 (4): 152–161.
- Liszczak G, Goldberg JM, Foyn H, Petersson EJ, Arnesen T, Marmorstein R (2013). "Molecular basis for N-terminal acetylation by the heterodimeric NatA complex". Nat. Struct. Mol. Biol. 20 (9): 1098–105.
- Starheim KK, Gromyko D, Velde R, Varhaug JE, Arnesen T (2009). "Composition and biological significance of the human Nalpha-terminal acetyltransferases". BMC Proc. 3 Suppl 6 (Suppl 6): S3.
- Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, Varhaug JE, Vandekerckhove J, Lillehaug JR, Sherman F, Gevaert K (2009). "Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans". Proc. Natl. Acad. Sci. U.S.A. 106 (20): 8157–8162.
- Arnesen T, Starheim KK, Van Damme P, Evjenth R, Dinh H, Betts MJ, Ryningen A, Vandekerckhove J, Gevaert K, Anderson D (2010). "The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation". Mol. Cell. Biol. 30 (8): 1898–1909.
- Hole K, Van Damme P, Dalva M, Aksnes H, Glomnes N, Varhaug JE, Lillehaug JR, Gevaert K, Arnesen T (2011). "The human N-alpha-acetyltransferase 40 (hNaa40p/hNatD) is conserved from yeast and N-terminally acetylates histones H2A and H4". PLoS ONE 6 (9): e24713.
- Gautschi M, Just S, Mun A, Ross S, Rücknagel P, Dubaquié Y, Ehrenhofer-Murray A, Rospert S (2003). "The yeast N(alpha)-acetyltransferase NatA is quantitatively anchored to the ribosome and interacts with nascent polypeptides". Mol. Cell. Biol. 23 (20): 7403–7414.
- Hollebeke J, Van Damme P, Gevaert K (2012). "N-terminal acetylation and other functions of Nα-acetyltransferases". Biol. Chem. 393 (4): 291–8.
- Hershko A, Heller H, Eytan E, Kaklij G, Rose IA (1984). "Role of the alpha-amino group of protein in ubiquitin-mediated protein breakdown". Proc. Natl. Acad. Sci. U.S.A. 81 (22): 7021–5.
- Hwang CS, Shemorry A, Varshavsky A (2010). "N-terminal acetylation of cellular proteins creates specific degradation signals". Science 327 (5968): 973–977.
- Behnia R, Panic B, Whyte JR, Munro S (2004). "Targeting of the Arf-like GTPase Arl3p to the Golgi requires N-terminal acetylation and the membrane protein Sys1p". Nat. Cell Biol. 6 (5): 405–413.
- Starheim KK, Gromyko D, Evjenth R, Ryningen A, Varhaug JE, Lillehaug JR, Arnesen T (2009). "Knockdown of human N alpha-terminal acetyltransferase complex C leads to p53-dependent apoptosis and aberrant human Arl8b localization". Mol. Cell. Biol. 29 (13): 3569–3581.
- Gromyko D, Arnesen T, Ryningen A, Varhaug JE, Lillehaug JR (2010). "Depletion of the human Nα-terminal acetyltransferase A induces p53-dependent apoptosis and p53-independent growth inhibition". Int. J. Cancer 127 (12): 2777–2789.
- Yi CH, Pan H, Seebacher J, Jang IH, Hyberts SG, Heffron GJ, Vander Heiden MG, Yang R, Li F, Locasale JW, Sharfi H, Zhai B, Rodriguez-Mias R, Luithardt H, Cantley LC, Daley GQ, Asara JM, Gygi SP, Wagner G, Liu CF, Yuan J (2011). "Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival". Cell 146 (4): 607–620.
- Kamita M, Kimura Y, Ino Y, Kamp RM, Polevoda B, Sherman F, Hirano H (2011). "N(α)-Acetylation of yeast ribosomal proteins and its effect on protein synthesis". J Proteomics 74 (4): 431–441.
- Yu M, Gong J, Ma M, Yang H, Lai J, Wu H, Li L, Li L, Tan D (2009). "Immunohistochemical analysis of human arrest-defective-1 expressed in cancers in vivo". Oncol. Rep. 21 (4): 909–15.
- Kalvik TV, Arnesen T (2013). "Protein N-terminal acetyltransferases in cancer". Oncogene 32 (3): 269–276.
- Sadoul K, Boyault C, Pabion M, Khochbin S (2008). "Regulation of protein turnover by acetyltransferases and deacetylases". Biochimie 90 (2): 306–12.
- Glozak MA, Sengupta N, Zhang X, Seto E (2005). "Acetylation and deacetylation of non-histone proteins". Gene 363: 15–23.
- Yang XJ, Seto E (2008). "Lysine acetylation: codified crosstalk with other posttranslational modifications". Mol. Cell 31 (4): 449–61.
- Eddé B, Denoulet P, de Néchaud B, Koulakoff A, Berwald-Netter Y, Gros F (1989). "Posttranslational modifications of tubulin in cultured mouse brain neurons and astroglia". Biol. Cell 65 (2): 109–117.
- Maruta H, Greer K, Rosenbaum JL (1986). "The acetylation of alpha-tubulin and its relationship to the assembly and disassembly of microtubules". J. Cell Biol. 103 (2): 571–579.
- Alberts, Bruce (March 2002). Molecular Biology of the Cell. Garland Science.
- Weinberg, Robert A. (2013). Biology of cancer. (2. ed.). [S.l.]: Garland Science.
- Brooks CL, Gu W (2011). "The impact of acetylation and deacetylation on the p53 pathway". Protein Cell 2 (6): 456–462.
- Tang Y, Zhao W, Chen Y, Zhao Y, Gu W (2008). "Acetylation is indispensable for p53 activation". Cell 133 (4): 612–626.
- Yamaguchi H, Woods NT, Piluso LG, Lee HH, Chen J, Bhalla KN, Monteiro A, Liu X, Hung MC, Wang HG (2009). "p53 acetylation is crucial for its transcription-independent proapoptotic functions". J. Biol. Chem. 284 (17): 11171–11183.
- Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004). "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science 303 (5659): 844–848.
- Shangary S, Wang S (2009). "Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy". Annu. Rev. Pharmacol. Toxicol. 49 (1): 223–241.
- Zajkowicz A, Krześniak M, Matuszczyk I, Głowala-Kosińska M, Butkiewicz D, Rusin M (2013). "Nutlin-3a, an MDM2 antagonist and p53 activator, helps to preserve the replicative potential of cancer cells treated with a genotoxic dose of resveratrol". Mol. Biol. Rep. 40 (8): 5013–5026.
- Kumamoto K, Spillare EA, Fujita K, Horikawa I, Yamashita T, Appella E, Nagashima M, Takenoshita S, Yokota J, Harris CC (2008). "Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence". Cancer Res. 68 (9): 3193–3203.
- Kreis, ed. by Thomas; Vale, Ronald (1999). Guidebook to the cytoskeletal and motor proteins (2. ed.). Oxford [u.a.]: Oxford Univ. Press.
- al.], Harvey Lodish ... [et (2013). Molecular cell biology (7th ed.). New York: W.H. Freeman and Co.
- Fojo, edited by Tito (2008). The role of microtubules in cell biology, neurobiology, and oncology ([Online-Ausg.] ed.). Totowa, N. J.: Humana Press.
- Friedmann DR, Aguilar A, Fan J, Nachury MV, Marmorstein R (2012). "Structure of the α-tubulin acetyltransferase, αTAT1, and implications for tubulin-specific acetylation". Proc. Natl. Acad. Sci. U.S.A. 109 (48): 19655–19660.
- Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002). "HDAC6 is a microtubule-associated deacetylase". Nature 417 (6887): 455–458.
- Teresa Carlomagno, ed. (2009). Tubulin-binding agents : synthetic, structural, and mechanistic insights. contributions by K.-H. Altmann. Berlin: Springer.
- Zito, edited by Thomas L. Lemke, David A. Williams; associate editors, Victoria F. Roche, S. William (2013). Foye's principles of medicinal chemistry (7th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.
- Müller-Decker, Friedrich Marks, Ursula Klingmüller, Karin (2009). Cellular signal processing : an introduction to the molecular mechanisms of signal transduction. New York: Garland Science.
- Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005). "Stat3 dimerization regulated by reversible acetylation of a single lysine residue". Science 307 (5707): 269–273.
- Lee H, Zhang P, Herrmann A, Yang C, Xin H, Wang Z, Hoon DS, Forman SJ, Jove R, Riggs AD, Yu H (2012). "Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation". Proc. Natl. Acad. Sci. U.S.A. 109 (20): 7765–7769.
Acetylation changes the free hydroxyls within the wood into acetyl groups. This is done by reacting the wood with acetic anhydride, which comes from acetic acid (known as vinegar when in its dilute form). When the free hydroxyl group is transformed to an acetyl group, the ability of the wood to absorb water is greatly reduced, rendering the wood more dimensionally stable and, because it is no longer digestible, extremely durable.
Since the beginning of the 20th century, acetylation of wood was researched as a method to upgrade the durability of wood in resistance against rotting processes and molds. Secondary benefits include the improvement of dimensional stability, improved surface hardness, and no decrease in mechanical properties due to the treatment. The physical properties of any material are determined by its chemical structure. Wood contains an abundance of chemical groups called “free hydroxyls”. Free hydroxyl groups adsorb and release water according to changes in the climatic conditions to which the wood is exposed. This is an explanation as to why wood swells and shrinks. It is also believed that the digestion of wood by enzymes initiates at the free hydroxyl sites – which is one of the principal reasons why wood is prone to decay. Accoya wood is a commercial, patented acetylated wood.
Acetylation of wood
Since the acetylation of STAT3 is important for its oncogenic activity and the fact that the level of acetylated STAT3 is high in cancer cells, it is implied that targeting acetylated STAT3 for chemoprevention and chemotherapy is a promising strategy. This strategy is supported by treating resveratrol, an inhibitor of acetylation of STAT3, in cancer cell line reverses aberrant CpG island methylation.
Therapeutic implications for cancer therapy
The acetylation of Lys685 of STAT3 is important for STAT3 homo-dimerization, which is essential for the DNA-binding and the transcriptional activation of oncogenes. The acetylation of STAT3 is catalyzed by histone acetyltransferase p300, and reversed by type 1 histone deacetylase. The lysine acetylation of STAT3 is also elevated in cancer cells.
Acetylation of STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is phosphorylated by receptor associated kinases, for example, Janus-family tyrosine kinases, and translocate to nucleus. STAT3 regulates several genes in response to growth factors and cytokines and play an important role in cell growth. Therefore, STAT3 facilitates oncogenesis in a variety of cell growth related pathways. On the other hand, it also play a role in the tumor suppressor.
Since microtubules play an important role in cell division, especially in the G2/M phase of the cell cycle, attempts have been made to impede microtubule function using small molecule inhibitors, which have been successfully used in clinics as cancer therapies. For example, the vinca alkaloids and taxanes selectively bind and inhibit microtubules, leading to cell cycle arrest. The identification of the crystal structure of acetylation of α-tubulin acetyl-transferase (α-TAT) also sheds a light on the discovery of small molecule that could modulate the stability or de-polymerization of tubulin. In other words, by targeting α-TAT, it is possible to prevent the tubulin from acetylation and result in the destabilization of tubulin, which is a similar mechanism for tubulin destabilizing agents.
Implications for cancer therapy
The acetylated residue of α-tubulin is K40, which is catalyzed by α-tubulin acetyl-transferase (α-TAT) in human. The acetylation of K40 on α-tubulin is a hallmark of stable microtubules. The active site residues D157 and C120 of α-TAT1 are responsible for the catalysis because of the shape complementary to α-Tubulin. In addition, some unique structural features such as β4-β5 hairpin, C-terminal loop, and α1-α2 loop regions are important for specific α-Tubulin molecular recognition. The reverse reaction of the acetylation is catalyzed by histone deacetylase 6.
Acetylation of tubulin
Since the major function of p53 is tumor suppressor, the idea that activation of p53 is an appealing strategy for cancer treatment. Nutlin-3 is a small molecule designed to target p53 and Mdm2 interaction that kept p53 from deactivation. Reports also shown that the cancer cell under the Nutilin-3a treatment, acetylation of lys 382 was observed in the c-terminal of p53.
Implications for cancer therapy
The acetylation of p53 is indispensable for its activation. It has been reported that the acetylation level of p53 will increase significantly when cell undergo stress. There are three major acetylation sites on p53: K164, K120 and C terminus. If only one of the acetylation sites is defected, the activation of p21 is still observed. However, if all three activation sites are blocked, the activation of p21 and the suppression of cell growth caused by p53 will be completely lost. In addition, the acetylation of p53 prevents its binding to the repressor Mdm2 on DNA. In addition, it is suggested that the p53 acetylation is crucial for its transcription-independent proapoptotic functions.
Acetylation of p53
The p53 protein is a tumor suppressor that plays an important role in the signal transactions in cells, especially in maintaining the stability of the genome by preventing mutation. Therefore, it is also known as “the guardian of the genome." In addition, it also regulates the cell cycle and arrests cell growth by activating a regulator of the cell cycle, p21. Under severe DNA damage, it also initiates programmed cell death.The function of p53 is negatively regulated by oncoprotein Mdm2. Studies suggested that Mdm2 will form a complex with p53 and prevent it from binding to specific p53-responsive genes.
The discovery of histone acetylation (and deacetylation) has been proved to be important in the transcriptional regulation in the field of epigenetics. However, histone is not the only protein that is highly regulated by posttranslational acetylation. In the following examples, we choose the following proteins that are important in biology that regulate the important signal transduction in biology by acetylation of proteins. In addition, the acetylation regulation on those proteins also related to human diseases and has a potential for the development for therapy.
The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation and deacetylation is a significant post-translational regulatory mechanism These regulatory mechanisms are analogous to phosphorylation and dephosphorylation by the action of kinases and phosphatases. Not only can the acetylation state of a protein modify its activity but there has been recent suggestion that this post-translational modification may also crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others for dynamic control of cellular signaling. The regulation of tubulin protein is an example of this in mouse neurons and astroglia. A tubulin acetyltransferase is located in the axoneme, and acetylates the α-tubulin subunit in an assembled microtubule. Once disassembled, this acetylation is removed by another specific deacetylase in the cell cytosol. Thus axonemal microtubules, which have a long half-life, carry a "signature acetylation," which is absent from cytosolic microtubules that have a shorter half-life.
Proteins are typically acetylated on lysine residues and this reaction relies on acetyl-coenzyme A as the acetyl group donor. In histone acetylation and deacetylation, histone proteins are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well.
Lysine acetylation and deacetylation
|Nat subunits||Cancer tissue||Expression pattern|
|hNaa10||lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma||high in tumors|
|hNaa10||lung cancer, breast cancer, pancreatic cancer, ovarian cancer||loss of heterozygosity in tumors|
|hNaa10||breast cancer, gastric cancer, lung cancer||high in primary tumors, but low with lymph node metastases|
|hNaa10||Non-small cell lung cancer||low in tumors|
|hNaa15||papillary thyroid carcinoma, gastric cancer||high in tumors|
|hNaa15||neuroblastoma||high in advanced stage tumors|
|hNaa11||hepatocellular carcinoma||loss of heterozygosity in tumors|
NATs have been suggested to act as both onco-proteins and tumor suppressors in human cancers, and NAT expression may be increased and decreased in cancer cells. Ectopic expression of hNaa10p increased cell proliferation and up regulation of gene involved in cell survival proliferation and metabolism. Overexpression of hNaa10p was in the urinary bladder cancer, breast cancer and cervical carcinoma. But a high level expression of hNaa10p could also suppress tumor growth and a reduced level of expressed hNaa10p is associated with a poor prognosis, large tumors and more lymph node metastases.
Ribosome proteins play an important role in the protein synthesis, which could also be N-terminal acetylated. The N-terminal acetylation of the ribosome proteins may have an effect on protein synthesis. A decrease of 27% and 23% in the protein synthesis rate was observed with NatA and NatB deletion strains. A reduction of translation fidelity was observed in the NatA deletion strain and a defect in ribosome was noticed in the NatB deletion strain.
Protein N-terminal acetylation has also been proved to relate with cell cycle regulation and apoptosis with protein knockdown experiments. Knockdown of the NatA or the NatC complex leads to the induction of p53-dependent apoptosis, which may indicate that the anti-apoptotic proteins were less or no longer functional because of reduced protein N-terminal acetylation. But in contrast, the caspase-2, which is acetylated by NatA, can interact with the adaptor protein RIP associated Ich-1/Ced-3 homologous protein with a death domain (RAIDD). This could activate caspase-2 and induce cell apoptosis.
Metabolism and apoptosis
 at the N-terminal of Arl3p, it can no longer localized to the Golgi membrane, indicating that Arl3p needs its natural N-terminal residues which could be acetylated for proper localization.Ala or Tyr is replaced by an Phe It requires its Nα-acetyl group for its targeting to the Golgi membrane by the interaction with Golgi membrane-residing protein Sys1p. If the