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Leah Gottlieb, Ronen Marmorstein
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...
April 23, 2018: Structure
Svein Isungset Støve, Marina Blenski, Asbjørg Stray-Pedersen, Klaas J Wierenga, Shalini N Jhangiani, Zeynep Coban Akdemir, David Crawford, Nina McTiernan, Line M Myklebust, Gabriela Purcarin, Rene McNall-Knapp, Alexandrea Wadley, John W Belmont, Jeffrey J Kim, James R Lupski, Thomas Arnesen
The NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of ~40% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions. In recent years several X-linked NAA10 variants have been associated with genetic disorders. We have identified a previously undescribed NAA10 c.215T>C p.(Ile72Thr) variant in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants...
May 10, 2018: European Journal of Human Genetics: EJHG
Hanyin Cheng, Avinash V Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F Rope, Margaret Yoon, Asbjørg Stray-Pedersen, Jennifer E Posey, Sarah R Crews, Mohammad K Eldomery, Zeynep Coban Akdemir, Andrea M Lewis, Vernon R Sutton, Jill A Rosenfeld, Erin Conboy, Katherine Agre, Fan Xia, Magdalena Walkiewicz, Mauro Longoni, Frances A High, Marjon A van Slegtenhorst, Grazia M S Mancini, Candice R Finnila, Arie van Haeringen, Nicolette den Hollander, Claudia Ruivenkamp, Sakkubai Naidu, Sonal Mahida, Elizabeth E Palmer, Lucinda Murray, Derek Lim, Parul Jayakar, Michael J Parker, Stefania Giusto, Emanuela Stracuzzi, Corrado Romano, Jennifer S Beighley, Raphael A Bernier, Sébastien Küry, Mathilde Nizon, Mark A Corbett, Marie Shaw, Alison Gardner, Christopher Barnett, Ruth Armstrong, Karin S Kassahn, Anke Van Dijck, Geert Vandeweyer, Tjitske Kleefstra, Jolanda Schieving, Marjolijn J Jongmans, Bert B A de Vries, Rolph Pfundt, Bronwyn Kerr, Samantha K Rojas, Kym M Boycott, Richard Person, Rebecca Willaert, Evan E Eichler, R Frank Kooy, Yaping Yang, Joseph C Wu, James R Lupski, Thomas Arnesen, Gregory M Cooper, Wendy K Chung, Jozef Gecz, Holly A F Stessman, Linyan Meng, Gholson J Lyon
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15...
April 9, 2018: American Journal of Human Genetics
Nina McTiernan, Svein Isungset Støve, Ingvild Aukrust, Marita Torrisen Mårli, Line M Myklebust, Gunnar Houge, Thomas Arnesen
BACKGROUND: The NAA10-NAA15 (NatA) protein complex is an N-terminal acetyltransferase responsible for acetylating ~ 40% of eukaryotic proteins. In recent years, NAA10 variants have been found in patients with an X-linked developmental disorder called Ogden syndrome in its most severe form and, in other familial or de novo cases, with variable degrees of syndromic intellectual disability (ID) affecting both sexes. CASE PRESENTATION: Here we report and functionally characterize a novel and de novo NAA10 (NM_003491...
March 20, 2018: BMC Medical Genetics
Rui Jiang, Chao Zhang, Rui Gu, Han Wu
Spinal cord injury (SCI) is caused by mechanical disruption of the spinal cord. This primary injury is followed by a devastating secondary SCI. It has been shown that various microRNAs (miRNAs) are involved in secondary SCI. The present study explored the role of miR-489-3p on secondary SCI, and its underlying mechanisms. First, we determined the expression of miR-489-3p in blood samples of SCI patients and healthy controls. Further experiments were performed on human neural cell lines, treated with bupivacaine to induce neuron damage...
May 1, 2017: Die Pharmazie
Xin Chen, Chao Yang, Shengli Xie, Edwin Cheung
Identification of prognostic biomarkers helps facilitate the prediction of patient outcomes as well as guide treatments. Accumulating evidence now suggests that long non-coding RNAs (lncRNAs) play key roles in tumor progression with diagnostic and prognostic values. However, little is known about the biological functions of lncRNAs and how they contribute to the pathogenesis of cancer. Herein, we performed weighted correlation network analysis (WGCNA) on 380 RNA-seq samples from prostate cancer patients to create networks comprising of microRNAs, lncRNAs, and protein-coding genes...
January 2, 2018: Oncotarget
Mandeep Sidhu, Lauren Brady, Mark Tarnopolsky, Gabriel M Ronen
BACKGROUND: Ogden syndrome is a rare X-linked disorder caused by pathogenic variants in the NAA10 gene. This syndrome, reported in just over 20 children, has been associated with dysmorphic features, failure to thrive, developmental impairments, hypotonia, and cardiac arrhythmias. PATIENT DESCRIPTION: We describe a 14-year-old girl who presented in infancy with hypotonia, global developmental delay, and dysmorphic features. She later developed autism spectrum disorder, epileptic encephalopathy, extrapyramidal signs, early morning lethargy with hypersomnolence, and hypertension with left ventricular hypertrophy...
July 19, 2017: Pediatric Neurology
Chen-Cheng Lee, Shih-Huan Peng, Li Shen, Chung-Fan Lee, Ting-Huei Du, Ming-Lun Kang, Guo-Liang Xu, Anup K Upadhyay, Xiaodong Cheng, Yu-Ting Yan, Yi Zhang, Li-Jung Juan
Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), but the underlying mechanism remains largely unclear. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorders, and maternal effect lethality, phenotypes commonly observed in defective genomic imprinting...
October 5, 2017: Molecular Cell
Felix Alexander Weyer, Andrea Gumiero, Karine Lapouge, Gert Bange, Jürgen Kopp, Irmgard Sinning
In eukaryotes, N-terminal acetylation is one of the most common protein modifications involved in a wide range of biological processes. Most N-acetyltransferase complexes (NATs) act co-translationally, with the heterodimeric NatA complex modifying the majority of substrate proteins. Here we show that the Huntingtin yeast two-hybrid protein K (HypK) binds tightly to the NatA complex comprising the auxiliary subunit Naa15 and the catalytic subunit Naa10. The crystal structures of NatA bound to HypK or to a N-terminal deletion variant of HypK were determined without or with a bi-substrate analogue, respectively...
June 6, 2017: Nature Communications
Xu Qian, Xinjian Li, Zhimin Lu
Macroautophagy/autophagy is a cellular defense response to stress conditions and is crucial for cell homeostasis maintenance. However, the precise mechanism underlying autophagy initiation, especially in response to glutamine deprivation and hypoxia, is yet to be explored. We recently discovered that PGK1 (phosphoglycerate kinase 1), a glycolytic enzyme, functions as a protein kinase, phosphorylating BECN1/Beclin 1 to initiate autophagy. Under glutamine deprivation or hypoxia stimulation, PGK1 is acetylated at K388 by NAA10/ARD1 in an MTOR-inhibition-dependent manner, leading to the interaction between PGK1 and BECN1 and the subsequent phosphorylation of BECN1 at S30 by PGK1...
July 3, 2017: Autophagy
Huiyu Xu, Yong Han, Bing Liu, Rong Li
N-α-acetyltransferase 10 (Naa10) displays alpha (N-terminal) acetyltransferase activity. It functions as a major modulator of cell growth and differentiation. Until now, a few downstream targets were found, but no studies have concerned about which gene is the early event of Naa10 downstream target. As we know, the earlier events may play more significant role in Naa10 pathway. Through construction of Naa10 stably knocked down H1299 cell line, we discovered cell morphological changes induced by Naa10. Moreover, potential function of Naa10 in cell morphogenesis was also indicated using cDNA microarray analysis of the Naa10 stably knock-down cell line...
December 2, 2016: Scientific Reports
Max J Dörfel, Han Fang, Jonathan Crain, Michael Klingener, Jake Weiser, Gholson J Lyon
Naa10 is an Nα -terminal acetyltransferase that, in a complex with its auxiliary subunit Naa15, co-translationally acetylates the α-amino group of newly synthetized proteins as they emerge from the ribosome. Roughly 40-50% of the human proteome is acetylated by Naa10, rendering this an enzyme one of the most broad substrate ranges known. Recently, we reported an X-linked disorder of infancy, Ogden syndrome, in two families harbouring a c.109 T > C (p.Ser37Pro) variant in NAA10. In the present study we performed in-depth characterization of a yeast model of Ogden syndrome...
January 2017: Yeast
Jinlin Feng, Ligeng Ma
Suspensor development is essential for early embryogenesis. The filamentous suspensor plays vital roles in supporting the embryo proper and in exchanging nutrients and information between the embryo proper and embryo sac. In addition, at the globular stage, the uppermost suspensor cell differentiates into the hypophysis, which generates the progenitors of the quiescent center and columella stem cells. In naa10 and naa15 mutant plants, suspensor cell identity was found to be abnormal and embryo development was disturbed, leading to embryonic lethality...
October 2, 2016: Plant Signaling & Behavior
Ravikumar Reddi, Venkateshwarlu Saddanapu, Dinesh Kumar Chinthapalli, Priyanka Sankoju, Prabhakar Sripadi, Anthony Addlagatta
Amino-terminal acetylation is a critical co-translational modification of the newly synthesized proteins in a eukaryotic cell carried out by six amino-terminal acetyltransferases (NATs). All NATs contain at least one catalytic subunit, and some contain one or two additional auxiliary subunits. For example, NatE is a complex of Naa10, Naa50, and Naa15 (auxiliary). In the present study, the crystal structure of human Naa50 suggested the presence of CoA and acetylated tetrapeptide (AcMMXX) that have co-purified with the protein...
September 23, 2016: Journal of Biological Chemistry
Jinlin Feng, Ruiqi Li, Junya Yu, Shuangshuang Ma, Chunyan Wu, Yan Li, Ying Cao, Ligeng Ma
Early embryonic development generates precursors of all major cell types in Arabidopsis. Among these precursors, the hypophysis divides asymmetrically to form the progenitors of the quiescent center and columella stem cells. A great deal has been learnt about the mechanisms that control the asymmetric division of the hypophysis and embryogenesis at the transcriptional level; however, no evidence of regulation at the co- or post-translational level has been reported. Here, we show that mutation of the catalytic subunit (Naa10) or auxiliary subunit (Naa15) of NatA, an N-terminal acetyltransferase that catalyzes protein N-terminal acetylation, produces an embryo-lethal phenotype...
August 2016: Journal of Experimental Botany
Svein Isungset Støve, Robert S Magin, Håvard Foyn, Bengt Erik Haug, Ronen Marmorstein, Thomas Arnesen
N-Terminal acetylation is a common and important protein modification catalyzed by N-terminal acetyltransferases (NATs). Six human NATs (NatA-NatF) contain one catalytic subunit each, Naa10 to Naa60, respectively. In contrast to the ribosome-associated NatA to NatE, NatF/Naa60 specifically associates with Golgi membranes and acetylates transmembrane proteins. To gain insight into the molecular basis for the function of Naa60, we developed an Naa60 bisubstrate CoA-peptide conjugate inhibitor, determined its X-ray structure when bound to CoA and inhibitor, and carried out biochemical experiments...
July 6, 2016: Structure
Chloé Saunier, Svein Isungset Støve, Bernt Popp, Bénédicte Gérard, Marina Blenski, Nicholas AhMew, Charlotte de Bie, Paula Goldenberg, Bertrand Isidor, Boris Keren, Bruno Leheup, Laetitia Lampert, Cyril Mignot, Kamer Tezcan, Grazia M S Mancini, Caroline Nava, Melissa Wasserstein, Ange-Line Bruel, Julien Thevenon, Alice Masurel, Yannis Duffourd, Paul Kuentz, Frédéric Huet, Jean-Baptiste Rivière, Marjon van Slegtenhorst, Laurence Faivre, Amélie Piton, André Reis, Thomas Arnesen, Christel Thauvin-Robinet, Christiane Zweier
N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated...
August 2016: Human Mutation
Robert S Magin, Zachary M March, Ronen Marmorstein
The N-terminal acetyltransferase NatA is a heterodimeric complex consisting of a catalytic subunit (Naa10/ARD1) and an auxiliary subunit (Naa15). NatA co-translationally acetylates the N termini of a wide variety of nascent polypeptides. In addition, Naa10 can act independently to posttranslationally acetylate a distinct set of substrates, notably actin. Recent structural studies of Naa10 have also revealed the molecular basis for N-terminal acetylation specificity. Surprisingly, recent reports claim that Naa10 may also acetylate lysine residues of diverse targets, including methionine sulfoxide reductase A, myosin light chain kinase, and Runt-related transcription factor 2...
March 4, 2016: Journal of Biological Chemistry
Hongju Yang, Qian Li, Jie Niu, Bai Li, Dejun Jiang, Zhihua Wan, Qingmei Yang, Fei Jiang, Ping Wei, Song Bai
miRNAs have been shown to play pivotal roles in the establishment and progression of colon cancer, but their underlying mechanisms are not fully understood. N-acetyltransferase NAA10 participates in many cellular processes, including tumorigenesis. Here we showed that miR-342-5p and miR-608 suppressed the tumorigenesis of colon cancer cells in vitro and in vivo by targeting NAA10 mRNA for degradation. Overexpression of miR-342-5p or miR-608 decreased NAA10 mRNA and protein levels and thereby suppressed cell proliferation, migration, and cell-cycle progression, as well as promoted apoptosis in SW480 and SW620 cells...
January 19, 2016: Oncotarget
Jillian P Casey, Svein I Støve, Catherine McGorrian, Joseph Galvin, Marina Blenski, Aimee Dunne, Sean Ennis, Francesca Brett, Mary D King, Thomas Arnesen, Sally Ann Lynch
We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA...
2015: Scientific Reports
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