Crystal Structures of Tubulin Acetyltransferase Reveal a Conserved Catalytic Core and the Plasticity of the Essential N Terminus

Kormendi, Vasilisa; Szyk, Agnieszka; Piszczek, Grzegorz; Roll-Mecak, Antonina

doi:10.1074/jbc.c112.421222

Cited by 34 publications

(36 citation statements)

References 33 publications

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“…Consistent with the sequence homology [46], the overall 3D structure of ATAT1 is very similar to that of the well-studied acetyltransferase GCN5 [52][53][54][55][56]. Different from GCN5, ATAT1 contains a basic substrate-binding pocket for recognition of four acidic residues of a-tubulin, Asp-33, -39, -46 and -47 [53].…”

Section: Tubulin Acetyltransferases and Deacetylases Identification Asupporting

confidence: 49%

“…Multiple structural studies have provided molecular insights into how human ATAT1 interacts with and acetylates a-tubulin (in a heterodimeric form with btubulin) and microtubules [52][53][54][55][56]. Consistent with the sequence homology [46], the overall 3D structure of ATAT1 is very similar to that of the well-studied acetyltransferase GCN5 [52][53][54][55][56].…”

Section: Tubulin Acetyltransferases and Deacetylases Identification Amentioning

confidence: 62%

“…2). Crystal structures of ATAT1 with and without acetyl coenzyme A binding have been determined [52][53][54][55][56] and form the basis for virtual screening of small-molecule inhibitors of these enzymes, which may be valuable for treating related diseases (Table 1). Neither mouse Atat1 nor Hdac6 is essential for survival.…”

Section: Conclusion and Future Directionmentioning

confidence: 99%

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Tubulin acetylation: responsible enzymes, biological functions and human diseases

Yang

2015

Cell. Mol. Life Sci.

213

184

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Microtubules have important functions ranging from maintenance of cell morphology to subcellular transport, cellular signaling, cell migration, and formation of cell polarity. At the organismal level, microtubules are crucial for various biological processes, such as viral entry, inflammation, immunity, learning and memory in mammals. Microtubules are subject to various covalent modifications. One such modification is tubulin acetylation, which is associated with stable microtubules and conserved from protists to humans. In the past three decades, this reversible modification has been studied extensively. In mammals, its level is mainly governed by opposing actions of α-tubulin acetyltransferase 1 (ATAT1) and histone deacetylase 6 (HDAC6). Knockout studies of the mouse enzymes have yielded new insights into biological functions of tubulin acetylation. Abnormal levels of this modification are linked to neurological disorders, cancer, heart diseases and other pathological conditions, thereby yielding important therapeutic implications. This review summarizes related studies and concludes that tubulin acetylation is important for regulating microtubule architecture and maintaining microtubule integrity. Together with detyrosination, glutamylation and other modifications, tubulin acetylation may form a unique 'language' to regulate microtubule structure and function.

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Section: Tubulin Acetyltransferases and Deacetylases Identification Asupporting

confidence: 49%

Section: Tubulin Acetyltransferases and Deacetylases Identification Amentioning

confidence: 62%

Section: Conclusion and Future Directionmentioning

confidence: 99%

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Tubulin acetylation: responsible enzymes, biological functions and human diseases

Yang

2015

Cell. Mol. Life Sci.

213

184

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“…1a). All annotated protein-coding Atat1 splice variants have the first seven exons in common (ENSMUS accession code G00000024426) and exons 3-7 encode the acetyltransferase domain [22][23][24][25] . We therefore designed a targeting construct whereby exons 1-6 were flanked with loxp sites to enable Cremediated tissue-specific deletion.…”

Section: Resultsmentioning

confidence: 99%

αTAT1 is the major α-tubulin acetyltransferase in mice

et al. 2013

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Post-translational modification of tubulin serves as a powerful means for rapidly adjusting the functional diversity of microtubules. Acetylation of the e-amino group of K40 in a-tubulin is one such modification that is highly conserved in ciliated organisms. Recently, aTAT1, a Gcn5-related N-acetyltransferase, was identified as an a-tubulin acetyltransferase in Tetrahymena and C. elegans. Here we generate mice with a targeted deletion of Atat1 to determine its function in mammals. Remarkably, we observe a loss of detectable K40 a-tubulin acetylation in these mice across multiple tissues and in cellular structures such as cilia and axons where acetylation is normally enriched. Mice are viable and develop normally, however, the absence of Atat1 impacts upon sperm motility and male mouse fertility, and increases microtubule stability. Thus, aTAT1 has a conserved function as the major a-tubulin acetyltransferase in ciliated organisms and has an important role in regulating subcellular specialization of subsets of microtubules.

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“…There are several potential mechanisms for how αTAT1 may access the acetylation site on the inside of the microtubule lumen: by copolymerization with tubulin at growing microtubule plus-ends (15), by transient openings in the lattice during microtubule breathing (13,16,17), or by microtubule end-entry (12,18). Copolymerization is not likely to be the primary mechanism for αTAT1 access, because stable microtubules are acetylated, and because αTAT1 is more active on polymerized microtubules than on free tubulin dimers (12,13,(19)(20)(21)(22)(23)(24)(25). Conversely, the other modes of access are possible (12,13,18).…”

mentioning

confidence: 99%

Mechanism of microtubule lumen entry for the α-tubulin acetyltransferase enzyme αTAT1

Coombes

Yamamoto

McClellan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

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Microtubules are structural polymers inside of cells that are subject to posttranslational modifications. These posttranslational modifications create functionally distinct subsets of microtubule networks in the cell, and acetylation is the only modification that takes place in the hollow lumen of the microtubule. Although it is known that the α-tubulin acetyltransferase (αTAT1) is the primary enzyme responsible for microtubule acetylation, the mechanism for how αTAT1 enters the microtubule lumen to access its acetylation sites is not well understood. By performing biochemical assays, fluorescence and electron microscopy experiments, and computational simulations, we found that αTAT1 enters the microtubule lumen through the microtubule ends, and through bends or breaks in the lattice. Thus, microtubule structure is an important determinant in the acetylation process. In addition, once αTAT1 enters the microtubule lumen, the mobility of αTAT1 within the lumen is controlled by the affinity of αTAT1 for its acetylation sites, due to the rapid rebinding of αTAT1 onto highly concentrated α-tubulin acetylation sites. These results have important implications for how acetylation could gradually accumulate on stable subsets of microtubules inside of the cell.microtubule | acetylation | biophysics | microscopy | modeling

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Crystal Structures of Tubulin Acetyltransferase Reveal a Conserved Catalytic Core and the Plasticity of the Essential N Terminus

Cited by 34 publications

References 33 publications

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Tubulin acetylation: responsible enzymes, biological functions and human diseases

αTAT1 is the major α-tubulin acetyltransferase in mice

Mechanism of microtubule lumen entry for the α-tubulin acetyltransferase enzyme αTAT1

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