6pw9

Structural highlights

Disease

[NAA10_HUMAN] Premature aging appearance-developmental delay-cardiac arrhythmia syndrome;Microphthalmia, Lenz type. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[HYPK_HUMAN] Has a chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT. Protects against HTT polyQ-mediated apoptosis in Neuro2a neuronal cells. Required for optimal NAA10-NAA15 complex-mediated N-terminal acetylation.^{[1] [2]} [NAA50_HUMAN] Probable catalytic component of the NAA11-NAA15 complex which displays alpha (N-terminal) acetyltransferase activity.^[3] [NAA10_HUMAN] Catalytic subunit of the N-terminal acetyltransferase A (NatA) complex which displays alpha (N-terminal) acetyltransferase activity (PubMed:15496142, PubMed:19826488, PubMed:19420222, PubMed:20145209, PubMed:27708256, PubMed:25489052). Acetylates amino termini that are devoid of initiator methionine (PubMed:19420222). The alpha (N-terminal) acetyltransferase activity may be important for vascular, hematopoietic and neuronal growth and development. Without NAA15, displays epsilon (internal) acetyltransferase activity towards HIF1A, thereby promoting its degradation (PubMed:12464182). Represses MYLK kinase activity by acetylation, and thus represses tumor cell migration (PubMed:19826488). Acetylates, and stabilizes TSC2, thereby repressing mTOR activity and suppressing cancer development (PubMed:20145209). Acetylates HSPA1A and HSPA1B at 'Lys-77' which enhances its chaperone activity and leads to preferential binding to co-chaperone HOPX (PubMed:27708256). Acts as a negative regulator of sister chromatid cohesion during mitosis (PubMed:27422821).^{[4] [5] [6] [7] [8] [9] [10] [11]} [NAA15_HUMAN] Auxillary subunit of the N-terminal acetyltransferase A (NatA) complex which displays alpha (N-terminal) acetyltransferase activity. The NAT activity may be important for vascular, hematopoietic and neuronal growth and development. Required to control retinal neovascularization in adult ocular endothelial cells. In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin promoter.^{[12] [13] [14]}

References

1. ↑ Raychaudhuri S, Sinha M, Mukhopadhyay D, Bhattacharyya NP. HYPK, a Huntingtin interacting protein, reduces aggregates and apoptosis induced by N-terminal Huntingtin with 40 glutamines in Neuro2a cells and exhibits chaperone-like activity. Hum Mol Genet. 2008 Jan 15;17(2):240-55. doi: 10.1093/hmg/ddm301. Epub 2007 Oct, 18. PMID:17947297 doi:http://dx.doi.org/10.1093/hmg/ddm301
2. ↑ Arnesen T, Starheim KK, Van Damme P, Evjenth R, Dinh H, Betts MJ, Ryningen A, Vandekerckhove J, Gevaert K, Anderson D. The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation. Mol Cell Biol. 2010 Apr;30(8):1898-909. doi: 10.1128/MCB.01199-09. Epub 2010 Feb , 12. PMID:20154145 doi:http://dx.doi.org/10.1128/MCB.01199-09
3. ↑ Arnesen T, Anderson D, Torsvik J, Halseth HB, Varhaug JE, Lillehaug JR. Cloning and characterization of hNAT5/hSAN: an evolutionarily conserved component of the NatA protein N-alpha-acetyltransferase complex. Gene. 2006 Apr 26;371(2):291-5. Epub 2006 Feb 28. PMID:16507339 doi:http://dx.doi.org/S0378-1119(05)00749-3
4. ↑ Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell. 2002 Nov 27;111(5):709-20. PMID:12464182
5. ↑ Arnesen T, Anderson D, Baldersheim C, Lanotte M, Varhaug JE, Lillehaug JR. Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. Biochem J. 2005 Mar 15;386(Pt 3):433-43. doi: 10.1042/BJ20041071. PMID:15496142 doi:http://dx.doi.org/10.1042/BJ20041071
6. ↑ Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, Varhaug JE, Vandekerckhove J, Lillehaug JR, Sherman F, Gevaert K. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8157-62. doi:, 10.1073/pnas.0901931106. Epub 2009 May 6. PMID:19420222 doi:http://dx.doi.org/10.1073/pnas.0901931106
7. ↑ Shin DH, Chun YS, Lee KH, Shin HW, Park JW. Arrest defective-1 controls tumor cell behavior by acetylating myosin light chain kinase. PLoS One. 2009 Oct 14;4(10):e7451. doi: 10.1371/journal.pone.0007451. PMID:19826488 doi:10.1371/journal.pone.0007451
8. ↑ Kuo HP, Lee DF, Chen CT, Liu M, Chou CK, Lee HJ, Du Y, Xie X, Wei Y, Xia W, Weihua Z, Yang JY, Yen CJ, Huang TH, Tan M, Xing G, Zhao Y, Lin CH, Tsai SF, Fidler IJ, Hung MC. ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. Sci Signal. 2010 Feb 9;3(108):ra9. doi: 10.1126/scisignal.2000590. PMID:20145209 doi:http://dx.doi.org/10.1126/scisignal.2000590
9. ↑ Myklebust LM, Van Damme P, Stove SI, Dorfel MJ, Abboud A, Kalvik TV, Grauffel C, Jonckheere V, Wu Y, Swensen J, Kaasa H, Liszczak G, Marmorstein R, Reuter N, Lyon GJ, Gevaert K, Arnesen T. Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Hum Mol Genet. 2015 Apr 1;24(7):1956-76. doi: 10.1093/hmg/ddu611. Epub 2014 Dec, 8. PMID:25489052 doi:http://dx.doi.org/10.1093/hmg/ddu611
10. ↑ Rong Z, Ouyang Z, Magin RS, Marmorstein R, Yu H. Opposing Functions of the N-terminal Acetyltransferases Naa50 and NatA in Sister-chromatid Cohesion. J Biol Chem. 2016 Sep 2;291(36):19079-91. doi: 10.1074/jbc.M116.737585. Epub 2016, Jul 15. PMID:27422821 doi:http://dx.doi.org/10.1074/jbc.M116.737585
11. ↑ Seo JH, Park JH, Lee EJ, Vo TT, Choi H, Kim JY, Jang JK, Wee HJ, Lee HS, Jang SH, Park ZY, Jeong J, Lee KJ, Seok SH, Park JY, Lee BJ, Lee MN, Oh GT, Kim KW. ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation. Nat Commun. 2016 Oct 6;7:12882. doi: 10.1038/ncomms12882. PMID:27708256 doi:http://dx.doi.org/10.1038/ncomms12882
12. ↑ Gendron RL, Good WV, Adams LC, Paradis H. Suppressed expression of tubedown-1 in retinal neovascularization of proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2001 Nov;42(12):3000-7. PMID:11687548
13. ↑ Willis DM, Loewy AP, Charlton-Kachigian N, Shao JS, Ornitz DM, Towler DA. Regulation of osteocalcin gene expression by a novel Ku antigen transcription factor complex. J Biol Chem. 2002 Oct 4;277(40):37280-91. Epub 2002 Jul 26. PMID:12145306 doi:http://dx.doi.org/10.1074/jbc.M206482200
14. ↑ Arnesen T, Anderson D, Baldersheim C, Lanotte M, Varhaug JE, Lillehaug JR. Identification and characterization of the human ARD1-NATH protein acetyltransferase complex. Biochem J. 2005 Mar 15;386(Pt 3):433-43. doi: 10.1042/BJ20041071. PMID:15496142 doi:http://dx.doi.org/10.1042/BJ20041071