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Nα-acetyltransferase 60 (NAA60) also known as NatF is a member of the N-terminal acetyltransferase (NAT) family of proteins.[1] NATs bind to acetyl-coenzyme A (Ac-CoA) as well as to the protein N-terminus, and enzymatically transfer the acetyl group from Ac-CoA to the free backbone amino group (NH3+) on the first residue of the protein.[2] NATs are mono- or multisubunit enzymes consisting of one catalytic subunit and up to two auxiliary subunits, however, only a catalytic subunit of NAA60 has been identified so far.[3]

Structure

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The crystal structure of NAA60 was solved in 2016 by Støve et al., however, without the C-terminal region due to difficulties purifying the whole protein.[4] The structure revealed an overall fold that is similar to the catalytic subunit of ribosome-associated NATs, and the two residues Y164 and Y165 of the β6-β7 loop important for peptide anchoring is conserved in NAA60 as in multiple NATs. Most similarities in the active site of NAA60 were found to NAA50. The two NATs share several residues that make up a hydrophobic core recognizing the Nt-Met of their substrates. However, this cavity is larger and more solvent exposed in NAA60 to accommodate larger and more polar residues in position 2 and 3 of its substrates[4].

Through biochemical analysis, the C-terminal end has been found to be important for binding to intracellular membranes but not for its biochemical function[5][4]. Two amphipathic α-helices near the C-terminus (residues 190-202 and 211-224) have been identified as mediators of the membrane interaction[6]

Subcellular localization

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NAA60 localizes to the Golgi apparatus, making it the only organellar bound NAT described to date.[5]. NAA10 through NAA50 all exhibit a cytoplasmic or nuclear localization[1]. Aksnes et al. show that both endogenous and overexpressed NAA60 colocalizes with the cis-Golgi marker GM130, as well as identifying it in vesicles colocalizing with markers for peroxisomes, endosomes, lysosomes, and secretory vesicles[5]

NAA60 has shown binding preference to membranes containing the phosphatidylinositol 4-phosphate lipid, possibly explaining its residens in Golgi membranes which are rich in these lipids[6]. All parts of the protein, including the GNAT domain, face the cytosol which limits NAA60`s catalytic activity to the cytosolic side of membranes[5][6].

Substrate specificity

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NAA60, together with NatC and NatE, is able to acetylate methionine starting N-termini followed by hydrophobic or amphiphatic-type amino acids (ML-, MI-, MF-, MY-, and MK-).[7][8] NAA60 show further substrate spesificity towards membrane proteins with their N-termini facing the cytosol[5]. From an N-terminomic analysis of NAA60 knock-down (KD) cells, 23 substrates of NAA60 were found, of which 21 were membrane proteins located either in the ER, plasma membrane, Golgi, mitochondria, or vesicular membranes[5].

Disease

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Recently, NAA60 were found to be important in brain phosphate homeostasis and it was identified as causative of the genetic disease primary familial brian calcification (PFBC).[9] PFBC is a neurodegenerative disease characterized by bilateral calcification distributed in the basal ganglia, thalamus, and cerebellum.[10][11][12] Symptoms could be generally grouped as movenet disorders, cognitive decline, and phychiatric disturbances[12].[13] In the study by Chelban and Aksnes et al. 10 individuals with PFBC from 7 different families were presented with biallelic variants of NAA60[9]. In NAA60 KD cells, one have previously observed Golgi fragmentation leading to the hypothesis that NAA60 is essential for the N-terminal acetylation of membrane proteins critical for normal Golgi function[5]. Chelban and Aksnes et al. show findings indicating a decrease in surface levels of SLC20A2 (another kown PFBC-related protein) when NAA60 is lacking, but no clear explanation of the molecular mechanism behind PFBC exists at this time[9].

References

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  1. ^ a b Aksnes, Henriette; McTiernan, Nina; Arnesen, Thomas (2023-07-15). "NATs at a glance". Journal of Cell Science. 136 (14). doi:10.1242/jcs.260766. ISSN 0021-9533. PMID 37462250.
  2. ^ Drazic, Adrian; Myklebust, Line M.; Ree, Rasmus; Arnesen, Thomas (2016). "The world of protein acetylation". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1864 (10): 1372–1401. doi:10.1016/j.bbapap.2016.06.007. PMID 27296530.
  3. ^ Liszczak, Glen; Goldberg, Jacob M; Foyn, Håvard; Petersson, E James; Arnesen, Thomas; Marmorstein, Ronen (2013). "Molecular basis for N-terminal acetylation by the heterodimeric NatA complex". Nature Structural & Molecular Biology. 20 (9): 1098–1105. doi:10.1038/nsmb.2636. ISSN 1545-9993. PMC 3766382. PMID 23912279.
  4. ^ a b c Støve, Svein Isungset; Magin, Robert S.; Foyn, Håvard; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas (2016). "Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation". Structure. 24 (7): 1044–1056. doi:10.1016/j.str.2016.04.020. PMC 4938767. PMID 27320834.
  5. ^ a b c d e f g Aksnes, Henriette; Van Damme, Petra; Goris, Marianne; Starheim, Kristian K.; Marie, Michaël; Støve, Svein Isungset; Hoel, Camilla; Kalvik, Thomas Vikestad; Hole, Kristine; Glomnes, Nina; Furnes, Clemens; Ljostveit, Sonja; Ziegler, Mathias; Niere, Marc; Gevaert, Kris (2015). "An Organellar Nα-Acetyltransferase, Naa60, Acetylates Cytosolic N Termini of Transmembrane Proteins and Maintains Golgi Integrity". Cell Reports. 10 (8): 1362–1374. doi:10.1016/j.celrep.2015.01.053. hdl:1956/10959. PMID 25732826.
  6. ^ a b c Aksnes, Henriette; Goris, Marianne; Strømland, Øyvind; Drazic, Adrian; Waheed, Qaiser; Reuter, Nathalie; Arnesen, Thomas (2017). "Molecular determinants of the N-terminal acetyltransferase Naa60 anchoring to the Golgi membrane". Journal of Biological Chemistry. 292 (16): 6821–6837. doi:10.1074/jbc.M116.770362. PMC 5399128. PMID 28196861.
  7. ^ Van Damme, Petra; Hole, Kristine; Pimenta-Marques, Ana; Helsens, Kenny; Vandekerckhove, Joël; Martinho, Rui G.; Gevaert, Kris; Arnesen, Thomas (2011-07-07). "NatF Contributes to an Evolutionary Shift in Protein N-Terminal Acetylation and Is Important for Normal Chromosome Segregation". PLOS Genetics. 7 (7): e1002169. doi:10.1371/journal.pgen.1002169. ISSN 1553-7404. PMC 3131286. PMID 21750686.
  8. ^ Van Damme, Petra; Evjenth, Rune; Foyn, Håvard; Demeyer, Kimberly; De Bock, Pieter-Jan; Lillehaug, Johan R.; Vandekerckhove, Joël; Arnesen, Thomas; Gevaert, Kris (2011-05-10). "Proteome-derived Peptide Libraries Allow Detailed Analysis of the Substrate Specificities of Nα-acetyltransferases and Point to hNaa10p as the Post-translational Actin Nα-acetyltransferase". Molecular & Cellular Proteomics. 10 (5): M110.004580. doi:10.1074/mcp.M110.004580. PMC 3098586. PMID 21383206.
  9. ^ a b c Chelban, Viorica; Aksnes, Henriette; Maroofian, Reza; LaMonica, Lauren C.; Seabra, Luis; Siggervåg, Anette; Devic, Perrine; Shamseldin, Hanan E.; Vandrovcova, Jana; Murphy, David; Richard, Anne-Claire; Quenez, Olivier; Bonnevalle, Antoine; Zanetti, M. Natalia; Kaiyrzhanov, Rauan (2024-03-13). "Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications". Nature Communications. 15 (1): 2269. Bibcode:2024NatCo..15.2269C. doi:10.1038/s41467-024-46354-0. ISSN 2041-1723. PMC 10937998. PMID 38480682.
  10. ^ Nicolas, Gaël; Pottier, Cyril; Charbonnier, Camille; Guyant-Maréchal, Lucie; Le Ber, Isabelle; Pariente, Jérémie; Labauge, Pierre; Ayrignac, Xavier; Defebvre, Luc; Maltête, David; Martinaud, Olivier; Lefaucheur, Romain; Guillin, Olivier; Wallon, David; Chaumette, Boris (2013-11-01). "Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification". Brain. 136 (11): 3395–3407. doi:10.1093/brain/awt255. ISSN 1460-2156. PMID 24065723.
  11. ^ Xu, Xuan; Sun, Hao; Luo, Junyu; Cheng, Xuewen; Lv, Wenqi; Luo, Wei; Chen, Wan-Jin; Xiong, Zhi-Qi; Liu, Jing-Yu (2023). "The Pathology of Primary Familial Brain Calcification: Implications for Treatment". Neuroscience Bulletin. 39 (4): 659–674. doi:10.1007/s12264-022-00980-0. ISSN 1673-7067. PMC 10073384. PMID 36469195.
  12. ^ a b Lemos, Roberta R.; Ramos, Eliana M.; Legati, Andrea; Nicolas, Gaël; Jenkinson, Emma M.; Livingston, John H.; Crow, Yanick J.; Campion, Dominique; Coppola, Giovanni; Oliveira, João R. M. (2015). "Update and Mutational Analysis of SLC20A2 : A Major Cause of Primary Familial Brain Calcification". Human Mutation. 36 (5): 489–495. doi:10.1002/humu.22778. PMID 25726928.
  13. ^ Carecchio, Miryam; Mainardi, Michele; Bonato, Giulia (2023). "The clinical and genetic spectrum of primary familial brain calcification". Journal of Neurology. 270 (6): 3270–3277. doi:10.1007/s00415-023-11650-0. ISSN 0340-5354. PMC 10188400. PMID 36862146.
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