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Mechanism of actin N-terminal acetylation.

<div class='caption-title'>NAA80 preferentially binds monomeric actin in vitro and in cells.</div>
<div class='caption-title'>Complex of actin-profilin is a preferred substrate of NAA80.</div>
<div class='caption-title'>Structural basis of NAA80 binding to actin-profilin.</div>
Rebowski G, Boczkowska M, Drazic A, Ree R, Goris M, Arnesen T, Dominguez R
OpenAccess logo Sci Adv 6 eaay8793 (2020)
Related entries: 6nbe, 6nbw

Cited: 29 times
EuropePMC logo PMID: 32284999

Abstract

About 80% of human proteins are amino-terminally acetylated (Nt-acetylated) by one of seven Nt-acetyltransferases (NATs). Actin, the most abundant protein in the cytoplasm, has its own dedicated NAT, NAA80, which acts posttranslationally and affects cytoskeleton assembly and cell motility. Here, we show that NAA80 does not associate with filamentous actin in cells, and its natural substrate is the monomeric actin-profilin complex, consistent with Nt-acetylation preceding polymerization. NAA80 Nt-acetylates actin-profilin much more efficiently than actin alone, suggesting that profilin acts as a chaperone for actin Nt-acetylation. We determined crystal structures of the NAA80-actin-profilin ternary complex, representing different actin isoforms and different states of the catalytic reaction and revealing the first structure of NAT-substrate complex at atomic resolution. The structural, biochemical, and cellular analysis of mutants shows how NAA80 has evolved to specifically recognize actin among all cellular proteins while targeting all six actin isoforms, which differ the most at the amino terminus.

Articles - 6nas mentioned but not cited (4)

  1. Mechanism of actin N-terminal acetylation. Rebowski G, Boczkowska M, Drazic A, Ree R, Goris M, Arnesen T, Dominguez R. Sci Adv 6 eaay8793 (2020)
  2. PFN2 and NAA80 cooperate to efficiently acetylate the N-terminus of actin. Ree R, Kind L, Kaziales A, Varland S, Dai M, Richter K, Drazic A, Arnesen T. J Biol Chem 295 16713-16731 (2020)
  3. NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay. Muffels IJJ, Wiame E, Fuchs SA, Massink MPG, Rehmann H, Musch JLI, Van Haaften G, Vertommen D, van Schaftingen E, van Hasselt PM. Brain Commun 3 fcab256 (2021)
  4. In silico studies reveal structural deviations of mutant profilin-1 and interaction with riluzole and edaravone in amyotrophic lateral sclerosis. Sadr AS, Eslahchi C, Ghassempour A, Kiaei M. Sci Rep 11 6849 (2021)


Reviews citing this publication (5)

  1. Protein N-Terminal Acetylation: Structural Basis, Mechanism, Versatility, and Regulation. Deng S, Marmorstein R. Trends Biochem Sci 46 15-27 (2021)
  2. Post-translational Modifications of the Protein Termini. Chen L, Kashina A. Front Cell Dev Biol 9 719590 (2021)
  3. Profilin: many facets of a small protein. Davey RJ, Moens PD. Biophys Rev 12 827-849 (2020)
  4. Posttranslational modifications of the cytoskeleton. MacTaggart B, Kashina A. Cytoskeleton (Hoboken) 78 142-173 (2021)
  5. Impact of Protein Nα-Modifications on Cellular Functions and Human Health. Chang YH. Life (Basel) 13 1613 (2023)

Articles citing this publication (20)

  1. Profilin choreographs actin and microtubules in cells and cancer. Pimm ML, Hotaling J, Henty-Ridilla JL. Int Rev Cell Mol Biol 355 155-204 (2020)
  2. N-Terminal Acetyltransferases Are Cancer-Essential Genes Prevalently Upregulated in Tumours. Koufaris C, Kirmizis A. Cancers (Basel) 12 E2631 (2020)
  3. The Final Maturation State of β-actin Involves N-terminal Acetylation by NAA80, not N-terminal Arginylation by ATE1. Drazic A, Timmerman E, Kajan U, Marie M, Varland S, Impens F, Gevaert K, Arnesen T. J Mol Biol 434 167397 (2022)
  4. Novel Au Carbene Complexes as Promising Multi-Target Agents in Breast Cancer Treatment. Ceramella J, Mariconda A, Sirignano M, Iacopetta D, Rosano C, Catalano A, Saturnino C, Sinicropi MS, Longo P. Pharmaceuticals (Basel) 15 507 (2022)
  5. Diversity from similarity: cellular strategies for assigning particular identities to actin filaments and networks. Boiero Sanders M, Antkowiak A, Michelot A. Open Biol 10 200157 (2020)
  6. Classification and phylogeny for the annotation of novel eukaryotic GNAT acetyltransferases. Krtenic B, Drazic A, Arnesen T, Reuter N. PLoS Comput Biol 16 e1007988 (2020)
  7. N-Heterocyclic Carbene (NHC) Silver Complexes as Versatile Chemotherapeutic Agents Targeting Human Topoisomerases and Actin. Mariconda A, Iacopetta D, Sirignano M, Ceramella J, Costabile C, Pellegrino M, Rosano C, Catalano A, Saturnino C, El-Kashef H, Aquaro S, Sinicropi MS, Longo P. ChemMedChem 17 e202200345 (2022)
  8. Mechanism of actin-dependent activation of nucleotidyl cyclase toxins from bacterial human pathogens. Belyy A, Merino F, Mechold U, Raunser S. Nat Commun 12 6628 (2021)
  9. Extended N-Terminal Acetyltransferase Naa50 in Filamentous Fungi Adds to Naa50 Diversity. Weidenhausen J, Kopp J, Ruger-Herreros C, Stein F, Haberkant P, Lapouge K, Sinning I. Int J Mol Sci 23 10805 (2022)
  10. Human NAA30 can rescue yeast mak3∆ mutant growth phenotypes. Drazic A, Varland S. Biosci Rep 41 BSR20202828 (2021)
  11. A solution to the long-standing problem of actin expression and purification. Ceron RH, Carman PJ, Rebowski G, Boczkowska M, Heuckeroth RO, Dominguez R. Proc Natl Acad Sci U S A 119 e2209150119 (2022)
  12. Cytosolic actin isoforms form networks with different rheological properties that indicate specific biological function. Nietmann P, Kaub K, Suchenko A, Stenz S, Warnecke C, Balasubramanian MK, Janshoff A. Nat Commun 14 7989 (2023)
  13. Differential N-terminal processing of beta and gamma actin. Chen L, Vedula P, Tang HY, Dong DW, Kashina AS. iScience 25 105186 (2022)
  14. N-terminal acetylation and arginylation of actin determines the architecture and assembly rate of linear and branched actin networks. Chin SM, Hatano T, Sivashanmugam L, Suchenko A, Kashina AS, Balasubramanian MK, Jansen S. J Biol Chem 298 102518 (2022)
  15. 5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics. Ceramella J, Iacopetta D, Caruso A, Mariconda A, Petrou A, Geronikaki A, Rosano C, Saturnino C, Catalano A, Longo P, Sinicropi MS. Pharmaceuticals (Basel) 16 353 (2023)
  16. Actin Isoform Composition and Binding Factors Fine-Tune Regulatory Impact of Mical Enzymes. Martin JL, Khan A, Grintsevich EE. Int J Mol Sci 24 16651 (2023)
  17. Computational study of the impact of nucleotide variations on highly conserved proteins: In the case of actin. Duong HTT, Suzuki H, Katagiri S, Shibata M, Arai M, Yura K. Biophys Physicobiol 19 e190025 (2022)
  18. Hydroxylation of the Acetyltransferase NAA10 Trp38 Is Not an Enzyme-Switch in Human Cells. Ree R, Krogstad K, McTiernan N, Jakobsson ME, Arnesen T. Int J Mol Sci 22 11805 (2021)
  19. Identification of a De Novo Heterozygous Missense ACTB Variant in Baraitser-Winter Cerebrofrontofacial Syndrome. Nie K, Huang J, Liu L, Lv H, Chen D, Fan W. Front Genet 13 828120 (2022)
  20. Optimized bisubstrate inhibitors for the actin N-terminal acetyltransferase NAA80. Myklebust LM, Baumann M, Støve SI, Foyn H, Arnesen T, Haug BE. Front Chem 11 1202501 (2023)


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