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Information on EC 2.3.1.108 - alpha-tubulin N-acetyltransferase and Organism(s) Homo sapiens and UniProt Accession Q5SQI0
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2.3.1.108 alpha-tubulin N-acetyltransferaseIUBMB Comments
The enzyme is conserved from protists to mammals and is present in flowering plants. In most organisms it acetylates L-lysine at position 40 of alpha-tubulin.
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Word Map
- 2.3.1.108
- trna
- histone
- chromatin
-
anticodons
-
wobble
- trnamet
- microtubule
- dysautonomia
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aminoacylated
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formylation
- cbp
- aminoacyl-trnas
- kluyveromyces
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zymocin
- methionyl-trna
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ikbkap
- trnaphe
- nua4
- rnapii
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six-subunit
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p-site
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non-histone
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complex-associated
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
elongator, lysine acetyltransferase, atat1, mec-17, tubulin acetyltransferase, alpha-tubulin acetyltransferase, atat-2, alpha-tubulin n-acetyltransferase 1, alpha-tubulin n-acetyltransferase, alpha-tubulin acetylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
acetyl-CoA:alpha-tubulin-L-lysine Ne-acetyltransferase
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alpha-tubulin acetylase
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alpha-tubulin acetyltransferase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acyl group transfer
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SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:[alpha-tubulin]-L-lysine N6-acetyltransferase
The enzyme is conserved from protists to mammals and is present in flowering plants. In most organisms it acetylates L-lysine at position 40 of alpha-tubulin.
CAS REGISTRY NUMBER
COMMENTARY
99889-90-4
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + [alpha-tubulin]-L-lysine40
CoA + [alpha-tubulin]-N6-acetyl-L-lysine40
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?
acetyl-CoA + alpha-tubulin L-lysine
CoA + alpha-tubulin N6-acetyl-L-lysine
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?
acetyl-CoA + alpha-tubulin L-lysine
CoA + alpha-tubulin N6-acetyl-L-lysine
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alpha-tubulin residue Ser38 is crucial for substrate recognition,whereas Asp39, Ile42, the glycine stretch (amino acid residues 4345) and Asp46 are also involved
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?
acetyl-CoA + cortactin
CoA + N-acetyl-cortactin
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ATAT1 acetylates, binds and colocalizes with cortactin at the adherent surface of MDA-MB-231 cells
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?
acetyl-CoA + [alpha-tubulin]-L-lysine
CoA + [alpha-tubulin]-N6-acetyl-L-lysine
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?
acetyl-CoA + [alpha-tubulin]-L-lysine
CoA + [alpha-tubulin]-N6-acetyl-L-lysine
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acetylation of alpha-tubulin mostly occurs on lysine residue 40, which is localized in the microtubule lumen
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?
additional information
?
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the enzyme shows tubulin-specific acetylation activity
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additional information
?
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the enzyme shows tubulin-specific acetylation activity
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additional information
?
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alphaTAT/MEC-17 is a lysine acetyltransferase for tubulin and not histones
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + [alpha-tubulin]-L-lysine40
CoA + [alpha-tubulin]-N6-acetyl-L-lysine40
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?
acetyl-CoA + cortactin
CoA + N-acetyl-cortactin
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ATAT1 acetylates, binds and colocalizes with cortactin at the adherent surface of MDA-MB-231 cells
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?
additional information
?
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alphaTAT/MEC-17 is a lysine acetyltransferase for tubulin and not histones
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?
acetyl-CoA + [alpha-tubulin]-L-lysine
CoA + [alpha-tubulin]-N6-acetyl-L-lysine
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?
acetyl-CoA + [alpha-tubulin]-L-lysine
CoA + [alpha-tubulin]-N6-acetyl-L-lysine
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acetylation of alpha-tubulin mostly occurs on lysine residue 40, which is localized in the microtubule lumen
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
analysis of KATi, bisubstrate analogues, natural compounds and synthetic derivatives, mechanism of action, structure-activity relationships, and pharmacokinetic/pharmacodynamic properties, overview
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additional information
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analysis of KATi, bisubstrate analogues, natural compounds and synthetic derivatives, mechanism of action, structure-activity relationships, and pharmacokinetic/pharmacodynamic properties, overview
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
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ATAT1 colocalizes with cortactin at the adherent surface of the cells, association of ATAT1 and cortactin at invadopodia, subcellular localization study, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
alphaTaT1 enters the microtubule lumen through the microtubule ends, and through bends or breaks in the lattice. AlphaTat1 is concentrated near th microtubule ends
additional information
ATAT1 dramatically changes its localization through the cell cycle, depending on the mitotic phase. In interphase, immunolabeled ATAT1 is observed in centrioles, nuclei, and basal bodies if the cells projected primary cilia. ATAT1 is intensely detected as clusters in the nuclei in the G1-G2 phase. In telophase, ATAT1 colocalizes with chromatids and spindle poles, and ultimately migrates to the daughter nucleus, newly synthesized centrioles, and midbody
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additional information
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ATAT1 dramatically changes its localization through the cell cycle, depending on the mitotic phase. In interphase, immunolabeled ATAT1 is observed in centrioles, nuclei, and basal bodies if the cells projected primary cilia. ATAT1 is intensely detected as clusters in the nuclei in the G1-G2 phase. In telophase, ATAT1 colocalizes with chromatids and spindle poles, and ultimately migrates to the daughter nucleus, newly synthesized centrioles, and midbody
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
the dysregulation of this enzyme activity is implicated in many human pathologies such as cancer, neurological and inflammatory disorders
physiological function
evolution
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distribution of alphaTAT/MEC-17 across all eukaryotic clades reveals that it was present in the last eukaryotic common ancestor, which was ciliated
malfunction
metabolism
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a balance of acetylation and deaceylation by ATAT1/HDAC6, histone deacetylase 6, enzymes with opposite activities regulates the migratory and invasive capacities of breast tumor cells
physiological function
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dynamics and distribution of MT1-MMP-positive endosomes require regulation of acetylation levels, ATAT1 tubulin acetyltransferase binds and regulates cortactin acetylation levels. Acetylation of alpha-tubulin mostly occurs on lysine residue 40, which is localized in the microtubule lumen. ATAT1 colocalizes with cortactin at the adherent surface of the cells and it is required for 2D migration and invasive migration of MDA-MB-231 cells in collagen matrix
additional information
physiological function
AcCoA and CoA each form a stable complex with human alphaTAT1 to maintain the protein integrity both in vivo and in vitro. The invariant residues Arg132 and Ser160 in alphaTAT1 participate in the stable interaction both with AcCoA and with CoA
physiological function
clathrin-coated pits control microtubule acetylation through a direct interaction of the alpha-tubulin acetyltransferase alphaTAT1 with the clathrin adaptor AP-2. About one-third of growing microtubule (+) ends contacts and pauses at clathrin-coated pits and loss of clathrin-coated pits decreased tubulin K40 acetylation levels. alphaTAT1 localises to clathrin-coated pits through a direct interaction with AP-2 that is required for microtubule acetylation. In migrating cells, the polarized orientation of acetylated microtubules correlates with clathrin-coated pits accumulation at the leading edge 10, and interaction of alphaTAT1 with AP-2 is required for directional migration
physiological function
despite the confined intraluminal location of microtubule residue Lys40, TAT efficiently scans the microtubule bidirectionally and acetylates stochastically without preference for ends. TAT catalytic activity, not constrained luminal diffusion, is rate limiting for acetylation
physiological function
alphaTaT1 enters the microtubule lumen through the microtubule ends, and through bends or breaks in the lattice. Once alphaTat1 enters the microtubule lumen, the mobility of alphaTat1 within the lumen is controlled by its affinity for its acetylation sites, due to the rapid rebinding of alphaTat1 onto highly concentrated alpha-tubulin acetylation sites. Microtuble acetylation occurs at microtubule ends and is facilitated by new latice openings
physiological function
lysine acetylation is a post-translational modification of both histone and nonhistone proteins that is catalyzed by lysine acetyltransferases and plays a key role in numerous biological contexts. Enzyme alphaTAT1 is involved in cell adhesion, migration, and invasion. It is the main KAT responsible for alpha-tubulin acetylation at Lys40 in higher organisms
physiological function
overexpression of MEC-17 in A-549 cells enhances the cell spreading area, suppresses pseudopods formation in a three-dimensional culture system, and inhibits cancer cell migratory and invasive ability and tumour metastasis by orthotopic lung cancer animal model. Morphological change and migration inhibition of cancer cells are accompanied by epithelial-mesenchymal transition repression, Golgi reorientation, and polarity disruption caused by alteration of Cdc42 activity via a decrease in Rho-GAP, ARHGAP21. A reduction in endogenous MEC-17 accelerates the pseudopods formation and epithelial-mesenchymal transition, and facilitates cell migration and invasion
malfunction
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a delay in cilium formation for cultured human cells depleted of alphaTAT/MEC-17
malfunction
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overexpression of ATAT1 phenocopies the effect of HDAC6 inhibition by trichostatin. Random invasive migration of cells in 3D collagen I is inhibited by 40-50% upon MT1-MMP or ATAT1 knockdown
additional information
despite having a tertiary structure similar to that of Gcn5, alphaTAT1 contains a relatively wide substrate binding pocket and unique structural elements that play an essential role in alpha-tubulin-specific acetylation, which is associated with many cellular processes connected to cancer dissemination such as cell adhesion, migration and invasion, tertiary enzyme structure in complex with acetyl-CoA (PDB ID 4gs4)
additional information
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despite having a tertiary structure similar to that of Gcn5, alphaTAT1 contains a relatively wide substrate binding pocket and unique structural elements that play an essential role in alpha-tubulin-specific acetylation, which is associated with many cellular processes connected to cancer dissemination such as cell adhesion, migration and invasion, tertiary enzyme structure in complex with acetyl-CoA (PDB ID 4gs4)
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ATAT_HUMAN
421
0
46810
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
cocrystal structures with bisubstrate analogs, consisting of a substrate peptide covalently linked to CoA through Lys40, to 1.35 A resolution. Substrate residue Lys40 is engaged in a suboptimal active site
crystal structure of the catalytic core of human MEC-17 in complex with its cofactor acetyl-CoA at 1.7 A resolution. The MEC-17 core adopts a canonical Gcn5-related N-acetyltransferase (GNAT) fold that is decorated with extensive surface loops. A large, evolutionarily conserved hydrophobic surface patch is critical for enzymatic activity
no significant changes are observed in the architecture of microtubules or the conformation of tubulin upon acetylation, based on protofilament distributions or microtubule helical lattice parameters. No clear differences in tubulin structure are detected between cryo-EM reconstructions of maximally deacetylated or acetylated microtubules. The effect of acetylation must be highly localized and affect interaction with proteins that bind directly to the lumen of the microtubule. alpha-TAT1 is able to interact with the outside of the microtubule, at least partly through the tubulin C-termini
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F105A
F183A
F186A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
F190A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
K162A
mutation in the acetyl-CoA binding pocket, mild effect on enzymatic activity
K169A
mutation in the acetyl-CoA binding pocket, mild effect on enzymatic activity
L104A
L164A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
L173A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
N73A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, discernable effect on catalytic activity
P178A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
Q131A
mutation in the acetyl-CoA binding pocket, mild effect on enzymatic activity
Q179A
R132A
S160A
S66A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, discernable effect on catalytic activity
V184A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
D157N
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site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
additional information
F105A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
F183A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
L104A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
Q179A
mutation in highly conserved surface patches adjacent to the substrate-binding groove, pronounced effetc on catalytic activity
R132A
mutation in the acetyl-CoA binding pocket, mild effect on enzymatic activity
R132A
mutation leads to a drastic misfolding of the isolated alphaTAT1 catalytic domain in the absence of CoA and AcCoA but not in the presence of excess amounts of either cofactor. Mutant is degraded much faster than the wild-type protein
S160A
mutation in the acetyl-CoA binding pocket, mild effect on enzymatic activity
S160A
mutation leads to a drastic misfolding of the isolated alphaTAT1 catalytic domain in the absence of CoA and AcCoA but not in the presence of excess amounts of either cofactor. Mutant is degraded much faster than the wild-type protein
additional information
expression of truncated variants, residues 1-193 and residues 1-236. Truncation mutant 1-193 exhibits a 3 times higher Km value than 1-236
additional information
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expression of truncated variants, residues 1-193 and residues 1-236. Truncation mutant 1-193 exhibits a 3 times higher Km value than 1-236
additional information
-
overexpression of ATAT1 phenocopies the effect of HDAC6 inhibition by trichostatin
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
ATAT1, DNA and amino acid sequence determination and analysis, stable functional expression of EGFP-ATAT1 and mutant ATAT1D157N in MDA-MB-231 cells and in HeLa cells
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Castro-Castro, A.; Janke, C.; Montagnac, G.; Paul-Gilloteaux, P.; Chavrier, P.
ATAT1/MEC-17 acetyltransferase and HDAC6 deacetylase control a balance of acetylation of alpha-tubulin and cortactin and regulate MT1-MMP trafficking and breast tumor cell invasion
Eur. J. Cell Biol.
91
950-960
2012
Homo sapiens
Leroux, M.
Tubulin acetyltransferase discovered: ciliary role in the ancestral eukaryote expanded to neurons in metazoans
Proc. Natl. Acad. Sci. USA
107
21238-21239
2010
Caenorhabditis elegans, Homo sapiens, Tetrahymena sp.
Yuzawa, S.; Kamakura, S.; Hayase, J.; Sumimoto, H.
Structural basis of cofactor-mediated stabilization and substrate recognition of the alpha-tubulin acetyltransferase alphaTAT1
Biochem. J.
467
103-113
2015
Homo sapiens (Q5SQI0)
Szyk, A.; Deaconescu, A.M.; Spector, J.; Goodman, B.; Valenstein, M.L.; Ziolkowska, N.E.; Kormendi, V.; Grigorieff, N.; Roll-Mecak, A.
Molecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase
Cell
157
1405-1415
2014
Homo sapiens (Q5SQI0)
Davenport, A.M.; Collins, L.N.; Chiu, H.; Minor, P.J.; Sternberg, P.W.; Hoelz, A.
Structural and functional characterization of the alpha-tubulin acetyltransferase MEC-17
J. Mol. Biol.
426
2605-2616
2014
Homo sapiens (Q5SQI0), Homo sapiens
Howes, S.C.; Alushin, G.M.; Shida, T.; Nachury, M.V.; Nogales, E.
Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure
Mol. Biol. Cell
25
257-266
2014
Homo sapiens (Q5SQI0)
Montagnac, G.; Meas-Yedid, V.; Irondelle, M.; Castro-Castro, A.; Franco, M.; Shida, T.; Nachury, M.V.; Benmerah, A.; Olivo-Marin, J.C.; Chavrier, P.
alphaTAT1 catalyses microtubule acetylation at clathrin-coated pits
Nature
502
567-570
2013
Homo sapiens (Q5SQI0)
Fiorentino, F.; Mai, A.; Rotili, D.
Lysine acetyltransferase inhibitors structure-activity relationships and potential therapeutic implications
Future Med. Chem.
10
1067-1091
2018
Homo sapiens (Q5SQI0), Homo sapiens
Nekooki-Machida, Y.; Nakakura, T.; Nishijima, Y.; Tanaka, H.; Arisawa, K.; Kiuchi, Y.; Miyashita, T.; Hagiwara, H.
Dynamic localization of alpha-tubulin acetyltransferase ATAT1 through the cell cycle in human fibroblastic KD cells
Med. Mol. Morphol.
51
217-226
2018
Homo sapiens (Q5SQI0), Homo sapiens
Coombes, C.; Yamamoto, A.; McClellan, M.; Reid, T.A.; Plooster, M.; Luxton, G.W.; Alper, J.; Howard, J.; Gardner, M.K.
Mechanism of microtubule lumen entry for the alpha-tubulin acetyltransferase enzyme alphaTAT1
Proc. Natl. Acad. Sci. USA
113
E7176-E7184
2016
Homo sapiens (Q5SQI0)
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