6c9m: Difference between revisions

Latest revision as of 14:59, 4 October 2023

The Human NatA (Naa10/Naa15) amino-terminal acetyltransferase complex

Structural highlights

6c9m is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:	1PE, ACE, IHP
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

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^[4]

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:https://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:https://dx.doi.org/10.1042/BJ20041071
↑ 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:https://dx.doi.org/10.1016/j.str.2018.04.003

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OCA

[1] 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

[2] 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:https://dx.doi.org/10.1074/jbc.M206482200

[3] 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:https://dx.doi.org/10.1042/BJ20041071

[4] 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:https://dx.doi.org/10.1016/j.str.2018.04.003

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[2]

[3]

[4]

@@ Line 1: / Line 1: @@
 ==The Human NatA (Naa10/Naa15) amino-terminal acetyltransferase complex==
-<StructureSection load='6c9m' size='340' side='right' caption='[[6c9m]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='6c9m' size='340' side='right'caption='[[6c9m]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6c9m]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C9M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C9M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6c9m]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6C9M FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[69c5|69c5]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6c9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c9m OCA], [https://pdbe.org/6c9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6c9m RCSB], [https://www.ebi.ac.uk/pdbsum/6c9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6c9m ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/N-terminal_amino-acid_N(alpha)-acetyltransferase_NatA N-terminal amino-acid N(alpha)-acetyltransferase NatA], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.255 2.3.1.255] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6c9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c9m OCA], [http://pdbe.org/6c9m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c9m RCSB], [http://www.ebi.ac.uk/pdbsum/6c9m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c9m ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[http://www.uniprot.org/uniprot/NAA10_HUMAN 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 ==
-[[http://www.uniprot.org/uniprot/NAA15_HUMAN 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.<ref>PMID:11687548</ref> <ref>PMID:12145306</ref> <ref>PMID:15496142</ref>  [[http://www.uniprot.org/uniprot/NAA10_HUMAN 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).<ref>PMID:12464182</ref> <ref>PMID:15496142</ref> <ref>PMID:19420222</ref> <ref>PMID:19826488</ref> <ref>PMID:20145209</ref> <ref>PMID:25489052</ref> <ref>PMID:27422821</ref> <ref>PMID:27708256</ref>
+[https://www.uniprot.org/uniprot/NAA15_HUMAN 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.<ref>PMID:11687548</ref> <ref>PMID:12145306</ref> <ref>PMID:15496142</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Gottlieb, L]]
+[[Category: Homo sapiens]]
-[[Category: Marmorstein, R]]
+[[Category: Large Structures]]
-[[Category: N-terminal acetylation]]
+[[Category: Gottlieb L]]
-[[Category: Nata]]
+[[Category: Marmorstein R]]
-[[Category: Protein complex]]
-[[Category: Transferase]]

6c9m: Difference between revisions

Latest revision as of 14:59, 4 October 2023

The Human NatA (Naa10/Naa15) amino-terminal acetyltransferase complex

Structural highlights

Function

Publication Abstract from PubMed

References

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