N-alpha-acetyltransferase 10 (NAA10) also known asNatA catalytic subunit Naa10 andarrest-defective protein 1 homolog A (ARD1A) is anenzymesubunit that in humans is encodedNAA10gene.[5][6]Together with its auxiliary subunitNaa15, Naa10 constitutes theNatA (Nα-acetyltransferase A) complex that specifically catalyzes the transfer of anacetyl group fromacetyl-CoA to theN-terminal primary amino group of certain proteins. In highereukaryotes, 5 otherN-acetyltransferase (NAT) complexes, NatB-NatF, have been described that differ both in substrate specificity and subunit composition.[7]
The humanNAA10 is located on chromosome Xq28 and contains 8exons, 2 encoding three differentisoforms derived fromalternate splicing.[8] Additionally, a processedNAA10 gene duplicationNAA11 (ARD2) has been identified that is expressed in several human cell lines;[9] however, later studies indicate that Naa11 is not expressed in the human cell linesHeLa andHEK293 or in cancerous tissues, andNAA11 transcripts were only detected intesticular andplacental tissues.[10] Naa11 has also been found in mouse, where it is mainly expressed in the testis.[11]NAA11 is located on chromosome 4q21.21 in human and 5 E3 in mouse, and only contains two exons. Mice have another Naa10-like paralog, Naa12. Naa12 has NAT activity and genetically compensates for loss of Naa10, while being Naa10/Naa12 null is embryonic lethal in mic.[12]
In mouse,NAA10 is located on chromosome X A7.3 and contains 9 exons. Two alternative splicing products of mouse Naa10, mNaa10235 and mNaa10225, were reported in NIH-3T3 and JB6 cells that may have different activities and function in different subcellular compartments.[13]
Homologues for Naa10 have been identified in almost all kingdoms of life analyzed, including plants,[14][15][16] fungi,[14][17]amoebozoa,[14]archaeabacteria[14][18][19][20] andprotozoa.[21][22] Ineubacteria, 3 Nα-acetyltransferases, RimI, RimJ and RimL, have been identified[23][24][25] but according to their low sequence identity with the NATs, it is likely that the RIM proteins do not have a common ancestor and evolved independently.[26][27]
Size-exclusion chromatography andcircular dichroism indicated that human Naa10 consists of a compact globular region comprising two thirds of the protein and a flexible unstructuredC-terminus.[28] X-ray crystal structure of the 100 kD holo-NatA (Naa10/Naa15) complex fromS. pombe showed that Naa10 adopts a typical GNAT fold containing a N-terminal α1–loop–α2 segment that features one large hydrophobic interface and exhibits interactions with its auxiliary subunit Naa15, a central acetyl CoA-binding region, and C-terminal segments that are similar to the corresponding regions in Naa50, another Nα-acetyltransferase.[29] The X-ray crystal structure of archaeal T. volcanium Naa10 has also been reported, revealing multiple distinct modes of acetyl-Co binding involving the loops between β4 and α3, including the P-loop.[20] Non-complexed (Naa15 unbound) Naa10 adopts a different fold: Leu22 and Tyr26 shift out of theactive site of Naa10, and Glu24 (important for substrate binding and catalysis of NatA) is repositioned by ~5 Å, resulting in a conformation that allows for the acetylation of a different subset of substrates.[29] AnX-ray crystal structure of human Naa10 in complex with Naa15 and HYPK has been reported.[30]
Naa10, as part of the NatA complex, is bound to theribosome and co-translationally acetylates proteins starting with small side chains such as Ser, Ala, Thr, Gly, Val and Cys, after the initiatormethionine (iMet) has been cleaved bymethionine aminopeptidases (MetAP).[33] Furthermore, post-translational acetylation by non-ribosome-associated Naa10 might occur. About 40-50 % of all proteins are potential NatA substrates.[7][34] Additionally, in a monomeric state, structural rearrangements of the substrate binding pocket Naa10 allow acetylation of N-termini with acidic side chains.[29][35] Furthermore, Nε-acetyltransferase activity[36][37][38][39][40][41][42] and N-terminal propionyltransferase activity[43] have been reported.
Despite the fact that Nα-terminal acetylation of proteins has been known for many years, the functional consequences of this modification are not well understood. However, accumulating evidence have linked Naa10 to various signaling pathways, includingWnt/β-catenin,[38][39][44][45]MAPK,[44]JAK/STAT,[46] andNF-κB,[47][48][49][50] thereby regulating various cellular processes, including cell migration,[51][52] cell cycle control,[53][54][55] DNA damage control,[49][56] caspase-dependent cell death,[56][57] p53 dependent apoptosis,[54] cell proliferation and autophagy[58] as well as hypoxia,[39][40][42][59][60] although there are some major discrepancies regarding hypoxia[61][62][63][64][65] and even isoform specific effects of Naa10 functions have been reported in mouse.[13][66]
Naa10 is essential inD. melanogaster,[67]C. elegans[68] andT. brucei.[21] InS. cerevisiae, Naa10 function is not essential but yNAA10Δ cells display severe defects including de-repression of the silent mating type locus (HML), failure to enter Go phase, temperature sensitivity, and impaired growth.[17][69] Naa10-knockout mice have very recently been reported to be viable, displaying a defect in bone development.[50]
In 2001 A c.109T>C (p.Ser37Pro) variant inNAA10 was identified in two unrelated families withOgden Syndrome, a X-linked disorder involving a distinct combination of an aged appearance, craniofacial anomalies,hypotonia, global developmental delays,cryptorchidism, andcardiac arrhythmias.[70] Patientfibroblasts displayed alteredmorphology, growth andmigration characteristics and molecular studies indicate that this S37P mutation disrupts the NatA complex and decreases Naa10 enzymatic activityin vitro andin vivo.[70][71][72]
Furthermore, two other mutations in Naa10 (R116W mutation in a boy and a V107F mutation in a girl) have been described in two unrelated families with sporadic cases of non-syndromic intellectual disabilities, postnatal growth failure, and skeletal anomalies.[73][74] The girl was reported as having delayed closure of the fontanels, delayed bone age, broad great toes, mild pectus carinatum, pulmonary artery stenosis, atrial septal defect,prolonged QT interval. The boy was reported as having small hands/feet, high arched palate, and wide interdental spaces.
Additionally, a splice mutation in theintron 7 splice donor site (c.471+2T→A) ofNAA10 was reported in a single family withLenz microphthalmia syndrome (LMS), a very rare, genetically heterogeneous X-linked recessive disorder characterized bymicrophthalmia oranophthalmia, developmental delay, intellectual disability, skeletal abnormalities and malformations of teeth, fingers and toes.[75] Patient fibroblasts displayed cell proliferation defects, dysregulation of genes involved inretinoic acid signaling pathway, such asSTRA6, and deficiencies inretinol uptake.[75]
Accumulating evidence suggests Naa10 function might regulate co-translational protein folding through the modulation of chaperone function, thereby affecting pathological formation of toxicamyloid aggregates inAlzheimer's disease or prion [PSI+] propagation in yeast.[76][77][78][79]
Further information on NAA10 related syndromes can be found atwww.naa10gene.com
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