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naa15

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Official Full Name
N(alpha)-acetyltransferase 15, NatA auxiliary subunit
Background
This gene encodes a protein of unknown function. However, similarity to proteins in yeast and other species suggests that this protein may be an N-acetyltransferase.
Synonyms
NAA15; N(alpha)-acetyltransferase 15, NatA auxiliary subunit; NARG1, NMDA receptor regulated 1; N-alpha-acetyltransferase 15, NatA auxiliary subunit; FLJ13340; NATH; TBDN100; tubedown-1; protein tubedown-1; NMDA receptor regulated 1; gastric cancer antig

Nα-terminal acetylation (NTA) is one of the most common protein modifications that occurs during protein synthesis and involves the transfer of an acetyl group from acetyl-coenzyme A to the protein alpha-amino group in many biologic processes. N-terminal acetyltransferase A (NatA) consists of the catalytic subunit Naa10 and the auxiliary subunit Naa15 and acetylates small side chains such as Ser, Ala, Thr, Gly, Val and Cys after the initiator methionine has been cleaved by methionine aminopeptidases.

The N-alpha-acetyltransferase 15 (NAA15) gene encodes an auxillary subunit of the NatA complex that displays alpha (N-terminal) acetyltransferase activity, which is thought to tether the complex to the ribosome for posttranslational modification of proteins as they exit the ribosome. It requires to control retinal neovascularization in adult ocular endothelial cells. In complex with XRCC6 and XRCC5 (Ku80), NAA15 up-regulates transcription from the osteocalcin promoter.

Fig.1. Human NatA complex. [1]

Mechanisms of gene

As a component of the NatA complex composed of NAA10 or probably NAA11 and NAA15, NAA15 interacts with XRCC6, NAA50 and XRCC5 and associates with HYPK when in a complex with NAA10. The subcellular location of NAA15 is mainly nucleus and other location is the cytoplasm. NAA15 expressed at high levels in testis and in ocular endothelial cells. It also found in brain (corpus callosum), heart, colon, bone marrow and at lower levels in most adult tissues, including thyroid, liver, pancreas, mammary and salivary glands, lung, ovary, urogenital system and upper gastrointestinal tract. NAA15 overexpressed in gastric cancer, in papillary thyroid carcinomas and in a Burkitt lymphoma cell line (Daudi). It specifically suppressed in abnormal proliferating blood vessels in eyes of patients with proliferative diabetic retinopathy.

The relationships between gene and major human diseases

  • Intellectual Disability (ID) [2]

ID is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In the study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. Previous study reported NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

  • Huntington's disease (HD) [3]

HD, also known as Huntington's chorea, is an inherited disorder that leads to death of brain cells. The earliest symptoms are often subtle problems with mood or mental abilities. The disease is caused by an autosomal dominant mutation in one of an individual's two copies of a gene named Huntingtin [4]. The NatA complex is composed of the catalytic subunit hNaa10p (hArd1) and the auxiliary subunit hNaa15p (hNat1/NATH). Previous study indicated that hNAA15 is required for the stability of huntingtin interacting protein K (HYPK) and both HYPK and NatA prevent Htt aggregation. Furthermore, this study demonstrated that HYPK is required for N-terminal acetylation of the known in vivo NatA substrate protein PCNP. Taken together, the data indicate that the physical interaction between HYPK and NatA seems to be of functional importance both for Htt aggregation and for N-terminal acetylation.

Conclusions

NAA15 is thought to tether the complex to the ribosome for posttranslational modification of proteins when they exit the ribosome. NAA15 is regulated by the N-methyl-D-aspartate class of glutamate receptors (NMDAR), which is responsible for the transmission of signals between neurons. The NAT activity may be important for vascular, hematopoietic and neuronal growth and development. Other function of NAA15 needed further research.

References:

  1. Gottlieb, L. and R. Marmorstein, Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. Structure, 2018. 26(7): p. 925-935.e8.
  2. Zhao, J.J., et al., Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. Am J Med Genet B Neuropsychiatr Genet, 2018. 177(1): p. 10-20.
  3. Arnesen, T., et al., The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation. Mol Cell Biol, 2010. 30(8): p. 1898-909.
  4. Dayalu, P. and R.L. Albin, Huntington Disease: Pathogenesis and Treatment. Neurologic Clinics, 2015. 33(1): p. 101-114.