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Wladek Minor - One of the best experts on this subject based on the ideXlab platform.
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insight into the 3d structure and substrate specificity of previously uncharacterized gnat superfamily Acetyltransferases from pathogenic bacteria
Biochimica et Biophysica Acta, 2017Co-Authors: Karolina A Majorek, W F Anderson, Wladek Minor, Tomasz Osinski, David Tran, Alina Revilla, Misty L KuhnAbstract:Members of the Gcn5-related N-acetyltransferase (GNAT) superfamily catalyze the acetylation of a wide range of small molecule and protein substrates. Due to their abundance in all kingdoms of life and diversity of their functions, they are implicated in many aspects of eukaryotic and prokaryotic physiology. Although numerous GNATs have been identified thus far, many remain structurally and functionally uncharacterized. The elucidation of their structures and functions is critical for broadening our knowledge of this diverse and important superfamily. In this work, we present the structural and kinetic analyses of two previously uncharacterized bacterial Acetyltransferases - SACOL1063 from Staphylococcus aureus strain COL and CD1211 from Clostridium difficile strain 630. Our structures of SACOL1063 show substantial flexibility of a loop that is likely responsible for substrate recognition and binding compared to structures of other homologs. In the CoA complex structure, we found two CoA molecules bound in both the canonical AcCoA/CoA-binding site and the acceptor-substrate-binding site. Our work also provides initial clues regarding the substrate specificity of these two enzymes; however, their native function(s) remain unknown. We found both proteins act as N- rather than O-Acetyltransferases and preferentially acetylate l-threonine. The combination of structural and kinetic analyses of these two previously uncharacterized GNATs provides fundamental knowledge and a framework on which future studies can be built to elucidate their native functions.
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structural functional and inhibition studies of a gcn5 related n acetyltransferase gnat superfamily protein pa4794 a new c terminal lysine protein acetyltransferase from pseudomonas aeruginosa
Journal of Biological Chemistry, 2013Co-Authors: Karolina A Majorek, Misty L Kuhn, Maksymilian Chruszcz, W F Anderson, Wladek MinorAbstract:The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related Acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of x-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nϵ amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Furthermore, we identified a number of molecules, including cephalosporin antibiotics, which are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with Ac-CoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis. Background: Gcn5-related N-Acetyltransferases (GNATs) are involved in small molecule and protein acetylation in all organisms. Results: Crystallographic and biochemical characterization of PA4794 is shown, including identification of substrates and inhibitors. Conclusion: PA4794 is a new bacterial C-terminal lysine protein acetyltransferase inhibited by cephalosporins. Significance: PA4794 is the first identified acetyltransferase specific for C-terminal lysine; identified interactions with cephalosporins may be of clinical relevance.
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structural functional and inhibition studies of a gcn5 related n acetyltransferase gnat superfamily protein pa4794 a new c terminal lysine protein acetyltransferase from pseudomonas aeruginosa
Journal of Biological Chemistry, 2013Co-Authors: Karolina A Majorek, Misty L Kuhn, Maksymilian Chruszcz, W F Anderson, Wladek MinorAbstract:The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related Acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of x-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nϵ amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Furthermore, we identified a number of molecules, including cephalosporin antibiotics, which are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with Ac-CoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis.
Yoshihiro Nakatani - One of the best experts on this subject based on the ideXlab platform.
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regulation of histone Acetyltransferases p300 and pcaf by the bhlh protein twist and adenoviral oncoprotein e1a
Cell, 1999Co-Authors: Yasuo Hamamori, Yoshihiro Nakatani, Vittorio Sartorelli, Vasily Ogryzko, Pier Lorenzo Puri, Jean Y J Wang, Larry KedesAbstract:Abstract Histone Acetyltransferases (HAT) play a critical role in transcriptional control by relieving repressive effects of chromatin, and yet how HATs themselves are regulated remains largely unknown. Here, it is shown that Twist directly binds two independent HAT domains of Acetyltransferases, p300 and p300/CBP–associated factor (PCAF), and directly regulates their HAT activities. The N terminus of Twist is a primary domain interacting with both Acetyltransferases, and the same domain is required for inhibition of p300-dependent transcription by Twist. Adenovirus E1A protein mimics the effects of Twist by inhibiting the HAT activities of p300 and PCAF. These findings establish a cogent argument for considering the HAT domains as a direct target for acetyltransferase regulation by both a cellular transcription factor and a viral oncoprotein.
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regulation of activity of the transcription factor gata 1 by acetylation
Nature, 1998Co-Authors: Joa Oyes, P G H Yfield, Yoshihiro Nakatani, Vasily OgryzkoAbstract:Modification of histones, DNA-binding proteins found in chromatin, by addition of acetyl groups occurs to a greater degree when the histones are associated with transcriptionally active DNA1,2. A breakthrough in understanding how this acetylation is mediated was the discovery that various transcriptional co-activator proteins have intrinsic histone acetyltransferase activity (for example, Gcn5p (ref. 3), PCAF4, TAFII250 (ref. 5) and p300/CBP6,7). These Acetyltransferases also modify certain transcription factors (TFIIEβ, TFIIF, EKLF and p53 (8–10)). GATA-1 is an important transcription factor in the haematopoietic lineage11 and is essential for terminal differentiation of erythrocytes and megakaryocytes12,13. It is associated in vivo with the acetyltransferase p300/CBP14. Here we report that GATA-1 is acetylated in vitro by p300. This significantly increases the amount of GATA-1 bound to DNA and alters the mobility of GATA-1–DNA complexes, suggestive of a conformational change in GATA-1. GATA-1 is also acetylated in vivo and acetylation directly stimulates GATA-1-dependent transcription. Mutagenesis of important acetylated residues shows that there is a relationship between the acetylation and in vivo function of GATA-1. Wepropose that acetylation of transcription factors can alter interactions between these factors and DNA and among different transcription factors, and is an integral part of transcription and differentiation processes.
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the histone acetyltransferase activity of human gcn5 and pcaf is stabilized by coenzymes
Journal of Biological Chemistry, 1997Co-Authors: Julio E Herrera, Yoshihiro Nakatani, Michael Bergel, Xiangjiao Yang, Michael BustinAbstract:Here we report that PCAF and human GCN5, two related type A histone Acetyltransferases, are unstable enzymes that under the commonly used assay conditions are rapidly and irreversibly inactivated. In addition, we report that free histone H1, although not acetylated in vivo, is a preferred and convenient in vitro substrate for the study of PCAF, human GCN5, and possibly other type A histone Acetyltransferases. Using either histone H1 or histone H3 as substrates, we find that preincubation with either acetyl-CoA or CoA stabilizes the acetyltransferase activities of PCAF, human GCN5 and an enzymatically active PCAF deletion mutant containing the C-terminal half of the protein. The stabilization requires the continuous presence of coenzyme, suggesting that the acetyltransferase-coenzyme complexes are stable, while the isolated apoenzymes are not. Human GCN5 and the N-terminal deletion mutant of PCAF are stabilized equally well by preincubation with either CoA or acetyl-CoA, while intact PCAF is better stabilized by acetyl-CoA than by CoA. Intact PCAF, but not the N-terminal truncation mutant or human GCN5, is autoacetylated. These findings raise the possibility that the intracellular concentrations of the coenzymes affect the stability and therefore the nuclear activity of these Acetyltransferases.
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nuclear receptor coactivator actr is a novel histone acetyltransferase and forms a multimeric activation complex with p caf and cbp p300
Cell, 1997Co-Authors: Hongwu Chen, Martin L. Privalsky, Yoshihiro Nakatani, Richard J Lin, Louis R Schiltz, Debabrata Chakravarti, Alyssa Nash, Laszlo Nagy, Ronald M EvansAbstract:Abstract We report here the identification of a novel cofactor, ACTR, that directly binds nuclear receptors and stimulates their transcriptional activities in a hormone- dependent fashion. ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex. In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family. Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone Acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex.
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the transcriptional coactivators p300 and cbp are histone Acetyltransferases
Cell, 1996Co-Authors: Vasily Ogryzko, Louis R Schiltz, Valya Russanova, Bruce H Howard, Yoshihiro NakataniAbstract:p300/CBP is a transcriptional adaptor that integrates signals from many sequence-specific activators via direct interactions. Various cellular and viral factors target p300/CBP to modulate transcription and/or cell cycle progression. One such factor, the cellular p300/CBP associated factor (PCAF), possesses intrinsic histone acetyltransferase activity. Here, we demonstrate that p300/CBP is not only a transcriptional adaptor but also a histone acetyltransferase. p300/CBP represents a novel class of Acetyltransferases in that it does not have the conserved motif found among various other Acetyltransferases. p300/CBP acetylates all four core histones in nucleosomes. These observations suggest that p300/CBP acetylates nucleosomes in concert with PCAF.
W F Anderson - One of the best experts on this subject based on the ideXlab platform.
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insight into the 3d structure and substrate specificity of previously uncharacterized gnat superfamily Acetyltransferases from pathogenic bacteria
Biochimica et Biophysica Acta, 2017Co-Authors: Karolina A Majorek, W F Anderson, Wladek Minor, Tomasz Osinski, David Tran, Alina Revilla, Misty L KuhnAbstract:Members of the Gcn5-related N-acetyltransferase (GNAT) superfamily catalyze the acetylation of a wide range of small molecule and protein substrates. Due to their abundance in all kingdoms of life and diversity of their functions, they are implicated in many aspects of eukaryotic and prokaryotic physiology. Although numerous GNATs have been identified thus far, many remain structurally and functionally uncharacterized. The elucidation of their structures and functions is critical for broadening our knowledge of this diverse and important superfamily. In this work, we present the structural and kinetic analyses of two previously uncharacterized bacterial Acetyltransferases - SACOL1063 from Staphylococcus aureus strain COL and CD1211 from Clostridium difficile strain 630. Our structures of SACOL1063 show substantial flexibility of a loop that is likely responsible for substrate recognition and binding compared to structures of other homologs. In the CoA complex structure, we found two CoA molecules bound in both the canonical AcCoA/CoA-binding site and the acceptor-substrate-binding site. Our work also provides initial clues regarding the substrate specificity of these two enzymes; however, their native function(s) remain unknown. We found both proteins act as N- rather than O-Acetyltransferases and preferentially acetylate l-threonine. The combination of structural and kinetic analyses of these two previously uncharacterized GNATs provides fundamental knowledge and a framework on which future studies can be built to elucidate their native functions.
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structural functional and inhibition studies of a gcn5 related n acetyltransferase gnat superfamily protein pa4794 a new c terminal lysine protein acetyltransferase from pseudomonas aeruginosa
Journal of Biological Chemistry, 2013Co-Authors: Karolina A Majorek, Misty L Kuhn, Maksymilian Chruszcz, W F Anderson, Wladek MinorAbstract:The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related Acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of x-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nϵ amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Furthermore, we identified a number of molecules, including cephalosporin antibiotics, which are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with Ac-CoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis. Background: Gcn5-related N-Acetyltransferases (GNATs) are involved in small molecule and protein acetylation in all organisms. Results: Crystallographic and biochemical characterization of PA4794 is shown, including identification of substrates and inhibitors. Conclusion: PA4794 is a new bacterial C-terminal lysine protein acetyltransferase inhibited by cephalosporins. Significance: PA4794 is the first identified acetyltransferase specific for C-terminal lysine; identified interactions with cephalosporins may be of clinical relevance.
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structural functional and inhibition studies of a gcn5 related n acetyltransferase gnat superfamily protein pa4794 a new c terminal lysine protein acetyltransferase from pseudomonas aeruginosa
Journal of Biological Chemistry, 2013Co-Authors: Karolina A Majorek, Misty L Kuhn, Maksymilian Chruszcz, W F Anderson, Wladek MinorAbstract:The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related Acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of x-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nϵ amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Furthermore, we identified a number of molecules, including cephalosporin antibiotics, which are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with Ac-CoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis.
Karolina A Majorek - One of the best experts on this subject based on the ideXlab platform.
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insight into the 3d structure and substrate specificity of previously uncharacterized gnat superfamily Acetyltransferases from pathogenic bacteria
Biochimica et Biophysica Acta, 2017Co-Authors: Karolina A Majorek, W F Anderson, Wladek Minor, Tomasz Osinski, David Tran, Alina Revilla, Misty L KuhnAbstract:Members of the Gcn5-related N-acetyltransferase (GNAT) superfamily catalyze the acetylation of a wide range of small molecule and protein substrates. Due to their abundance in all kingdoms of life and diversity of their functions, they are implicated in many aspects of eukaryotic and prokaryotic physiology. Although numerous GNATs have been identified thus far, many remain structurally and functionally uncharacterized. The elucidation of their structures and functions is critical for broadening our knowledge of this diverse and important superfamily. In this work, we present the structural and kinetic analyses of two previously uncharacterized bacterial Acetyltransferases - SACOL1063 from Staphylococcus aureus strain COL and CD1211 from Clostridium difficile strain 630. Our structures of SACOL1063 show substantial flexibility of a loop that is likely responsible for substrate recognition and binding compared to structures of other homologs. In the CoA complex structure, we found two CoA molecules bound in both the canonical AcCoA/CoA-binding site and the acceptor-substrate-binding site. Our work also provides initial clues regarding the substrate specificity of these two enzymes; however, their native function(s) remain unknown. We found both proteins act as N- rather than O-Acetyltransferases and preferentially acetylate l-threonine. The combination of structural and kinetic analyses of these two previously uncharacterized GNATs provides fundamental knowledge and a framework on which future studies can be built to elucidate their native functions.
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structural functional and inhibition studies of a gcn5 related n acetyltransferase gnat superfamily protein pa4794 a new c terminal lysine protein acetyltransferase from pseudomonas aeruginosa
Journal of Biological Chemistry, 2013Co-Authors: Karolina A Majorek, Misty L Kuhn, Maksymilian Chruszcz, W F Anderson, Wladek MinorAbstract:The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related Acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of x-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nϵ amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Furthermore, we identified a number of molecules, including cephalosporin antibiotics, which are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with Ac-CoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis. Background: Gcn5-related N-Acetyltransferases (GNATs) are involved in small molecule and protein acetylation in all organisms. Results: Crystallographic and biochemical characterization of PA4794 is shown, including identification of substrates and inhibitors. Conclusion: PA4794 is a new bacterial C-terminal lysine protein acetyltransferase inhibited by cephalosporins. Significance: PA4794 is the first identified acetyltransferase specific for C-terminal lysine; identified interactions with cephalosporins may be of clinical relevance.
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structural functional and inhibition studies of a gcn5 related n acetyltransferase gnat superfamily protein pa4794 a new c terminal lysine protein acetyltransferase from pseudomonas aeruginosa
Journal of Biological Chemistry, 2013Co-Authors: Karolina A Majorek, Misty L Kuhn, Maksymilian Chruszcz, W F Anderson, Wladek MinorAbstract:The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related Acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of x-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nϵ amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Furthermore, we identified a number of molecules, including cephalosporin antibiotics, which are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with Ac-CoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis.
Ronen Marmorstein - One of the best experts on this subject based on the ideXlab platform.
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molecular basis for cohesin acetylation by establishment of sister chromatid cohesion n acetyltransferase esco1
Journal of Biological Chemistry, 2016Co-Authors: Yadilette Riveracolon, Andrew Maguire, Glen Liszczak, Adam S Olia, Ronen MarmorsteinAbstract:Abstract Protein acetylation is a prevalent posttranslational modification that is regulated by diverse acetyltransferase enzymes. While histone Acetyltransferases (HATs) have been well characterized both structurally and mechanistically, far less is known about non-histone acetyltransferase enzymes. The human ESCO1 and ESCO2 paralogs acetylate the cohesin complex subunit SMC3 to regulate the separation of sister chromatids during mitosis and meiosis. Missense mutations within the acetyltransferase domain of these proteins correlate with diseases, including endometrial cancers and Roberts Syndrome. Despite their biological importance, the mechanisms underlying acetylation by the ESCO proteins are not understood. Here, we report the X-ray crystal structure of the highly conserved zinc finger-acetyltransferase moiety of ESCO1 with accompanying structure-based mutagenesis and biochemical characterization. We find that the ESCO1acetyltransferase core is structurally homologous to the Gcn5 HAT, but contains unique additional features including a zinc finger and a ~40-residue loop region that appear to play roles in protein stability and SMC3 substrate binding. We identify key residues that play roles in substrate binding and catalysis, and rationalize the functional consequences of disease-associated mutations. Together, these studies reveal the molecular basis for SMC3 acetylation by ESCO1 and have broader implications for understanding the structure/function of non-histone Acetyltransferases.
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crystal structure of the histone acetyltransferase domain of the human pcaf transcriptional regulator bound to coenzyme a
The EMBO Journal, 1999Co-Authors: Adrienne Clements, Shelley L. Berger, Lian Wang, J R Rojas, Raymond C Trievel, Ronen MarmorsteinAbstract:The human p300/CBP‐associating factor, PCAF, mediates transcriptional activation through its ability to acetylate nucleosomal histone substrates as well as transcriptional activators such as p53. We have determined the 2.3 A crystal structure of the histone acetyltransferase (HAT) domain of PCAF bound to coenzyme A. The structure reveals a central protein core associated with coenzyme A binding and a pronounced cleft that sits over the protein core and is flanked on opposite sides by the N‐ and C‐terminal protein segments. A correlation of the structure with the extensive mutagenesis data for PCAF and the homologous yeast GCN5 protein implicates the cleft and the N‐ and C‐terminal protein segments as playing an important role in histone substrate binding, and a glutamate residue in the protein core as playing an essential catalytic role. A structural comparison with the coenzyme‐bound forms of the related N ‐Acetyltransferases, HAT1 (yeast histone acetyltransferase 1) and SmAAT ( Serratia marcescens aminoglycoside 3‐ N ‐acetyltransferase), suggests the mode of substrate binding and catalysis by these enzymes and establishes a paradigm for understanding the structure–function relationships of other enzymes that acetylate histones and transcriptional regulators to promote activated transcription.
