N-alpha-acetyltransferase 10

N-alpha-acetyltransferase 10 (NAA10) also known as NatA catalytic subunit Naa10 and arrest-defective protein 1 homolog A (ARD1A) is an is_associated_with::enzyme that in humans is encoded NAA10 is_associated_with::gene. Together with its auxiliary subunit Naa15, Naa10 constitutes the NatA (Nα-acetyltransferase A) complex that specifically catalyzes the transfer of an acetyl group from is_associated_with::acetyl-CoA to the is_associated_with::N-terminal primary amino group of certain proteins. In higher eukaryotes, 5 other is_associated_with::N-acetyltransferase (NAT) complexes, NatB-NatF, have been described that differ both in substrate specificity and subunit composition.

Gene and transcripts
The human NAA10 is located on chromosome Xq28 and is encoded by 8 is_associated_with::exons 2 encoding three different isoforms derived from is_associated_with::alternate splicing. Additionally, a processed NAA10 gene duplication NAA11 (ARD2) has been identified that is expressed in several human cell lines; however, later studies indicate that Naa11 is not expressed in the human cell lines is_associated_with::HeLa and HEK293 or in cancerous tissues, and NAA11 transcripts were only detected in is_associated_with::testicular and is_associated_with::placental tissues. Naa11 has also been found in mouse, where it is mainly expressed in the testis. NAA11 is located on chromosome 4q21.21 in human and 5 E3 in mouse, and only contains two exons.

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.

Homologues for Naa10 have been identified in almost all kingdoms of life analyzed, including plants, fungi, is_associated_with::amoebozoa, is_associated_with::archaeabacteria  and is_associated_with::protozoa. In is_associated_with::eubacteria, 3 Nα-acetyltransferases, RimI, RimJ and RimL, have been identified  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.

Structure
To date, no is_associated_with::X-ray crystal structure of the human Naa10 has been reported. However, is_associated_with::size-exclusion chromatography and is_associated_with::circular dichroism indicated that human Naa10 consists of a compact globular region comprising two thirds of the protein and a flexible unstructured is_associated_with::C-terminus. Furthermore, the recent X-ray crystal structure of the 100 kD holo-NatA (Naa10/Naa15) complex from S. 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. 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. Interestingly, non-complexed (Naa15 unbound) Naa10 adopts a different fold: Leu22 and Tyr26 shift out of the active 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.

A functional is_associated_with::nuclear localization signal in the is_associated_with::C-terminus of hNaa10 between residues 78 and 83 (KRSHRR) has been described.

Function
Naa10, as part of the NatA complex, is bound to the is_associated_with::ribosome and co-translationally acetylates proteins starting with small side chains such as Ser, Ala, Thr, Gly, Val and Cys, after the initiator is_associated_with::methionine (iMet) has been cleaved by is_associated_with::methionine aminopeptidases (MetAP). Furthermore, post-translational acetylation by non-ribosome-associated Naa10 might occur. About 40-50 % of all proteins are potential NatA substrates. Additionally, in a monomeric state, structural rearrangements of the substrate binding pocket Naa10 allow acetylation of N-termini with acidic side chains. Furthermore, Nε-acetyltransferase activity    and N-terminal propionyltransferase activity 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, including Wnt/β-catenin, MAPK, JAK/STAT, and is_associated_with::NF-κB,   thereby regulating various cellular processes, including cell migration,  cell cycle control, DNA damage control, caspase-dependent cell death, p53 dependent apoptosis, cell proliferation and autophagy as well as hypoxia,    although there are some major discrepancies regarding hypoxia     and even isoform specific effects of Naa10 functions have been reported in mouse.

Naa10 is essential in is_associated_with::D. melanogaster, is_associated_with::C. elegans and T. brucei. In is_associated_with::S. 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. Naa10-knockout mice have very recently been reported to be viable, displaying a defect in bone development.

Disease
Recently, a c.109T>C (p.Ser37Pro) variant in NAA10 was identified in two unrelated families with is_associated_with::Ogden Syndrome, a X-linked disorder involving a distinct combination of an aged appearance, craniofacial anomalies, is_associated_with::hypotonia, global developmental delays, is_associated_with::cryptorchidism, and is_associated_with::cardiac arrhythmias. Patient is_associated_with::fibroblasts displayed altered morphology, growth and migration characteristics and molecular studies indicate that this S37P mutation disrupts the NatA complex and decreases Naa10 enzymatic activity in vitro and in vivo.

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. 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, is_associated_with::prolonged QT interval. The boy was reported as having small hands/feet, high arched palate, and wide interdental spaces.

Additionally, a splice mutation in the is_associated_with::intron 7 splice donor site (c.471+2T→A) of NAA10 was reported in a single family with is_associated_with::Lenz microphthalmia syndrome (LMS), a very rare, genetically heterogeneous X-linked recessive disorder characterized by is_associated_with::microphthalmia or is_associated_with::anophthalmia, developmental delay, intellectual disability, skeletal abnormalities and malformations of teeth, fingers and toes. Patient fibroblasts displayed cell proliferation defects, dysregulation of genes involved in is_associated_with::retinoic acid signaling pathway, such as is_associated_with::STRA6, and deficiencies in is_associated_with::retinol uptake.

Accumulating evidence suggests Naa10 function might regulate co-translational protein folding through the modulation of chaperone function, thereby affecting pathological formation of toxic is_associated_with::amyloid aggregates in is_associated_with::Alzheimer's disease or prion [PSI+] propagation in yeast.