| 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
[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.[1] [2] [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]
Publication Abstract from PubMed
Co-translational N-terminal protein acetylation regulates many protein functions including degradation, folding, interprotein interactions, and targeting. Human NatA (hNatA), one of six conserved metazoan N-terminal acetyltransferases, contains Naa10 catalytic and Naa15 auxiliary subunits, and associates with the intrinsically disordered Huntingtin yeast two-hybrid protein K (HYPK). We report on the crystal structures of hNatA and hNatA/HYPK, and associated biochemical and enzymatic analyses. We demonstrate that hNatA contains unique features: a stabilizing inositol hexaphosphate (IP6) molecule and a metazoan-specific Naa15 domain that mediates high-affinity HYPK binding. We find that HYPK harbors intrinsic hNatA-specific inhibitory activity through a bipartite structure: a ubiquitin-associated domain that binds a hNaa15 metazoan-specific region and an N-terminal loop-helix region that distorts the hNaa10 active site. We show that HYPK binding blocks hNaa50 targeting to hNatA, likely limiting Naa50 ribosome localization in vivo. These studies provide a model for metazoan NAT activity and HYPK regulation of N-terminal acetylation.
Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK.,Gottlieb L, Marmorstein R Structure. 2018 Apr 23. pii: S0969-2126(18)30128-X. doi:, 10.1016/j.str.2018.04.003. PMID:29754825[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Gottlieb L, Marmorstein R. Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. Structure. 2018 Apr 23. pii: S0969-2126(18)30128-X. doi:, 10.1016/j.str.2018.04.003. PMID:29754825 doi:http://dx.doi.org/10.1016/j.str.2018.04.003
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