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000856721 1001_ $$00000-0003-4738-0656$$aHalawani, Dalia$$b0
000856721 245__ $$aStructural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains
000856721 260__ $$aBethesda, Md.$$bSoc.72889$$c2018
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000856721 520__ $$aAminoacyl-tRNA synthetases are ubiquitous, evolutionarilyconserved enzymes catalyzing the conjugation of amino acidsonto cognate tRNAs. During eukaryotic evolution, tRNA syn-thetases have been the targets of persistent structural modifica-tions. These modifications can be additive, as in the evolution-ary acquisition of noncatalytic domains, or subtractive, as in thegeneration of truncated variants through regulated mechanismssuch as proteolytic processing, alternative splicing, or codingregion polyadenylation. A unique variant is the human glu-tamyl-prolyl-tRNA synthetase (EPRS) consisting of two fusedsynthetases joined by a linker containing three copies of theWHEP domain (termed by its presence in tryptophanyl-, histi-dyl-, and glutamyl-prolyl-tRNA synthetases). Here, we identifysite-selective proteolysis as a mechanism that severs the linkagebetween the EPRS synthetases in vitro and in vivo. Caspaseaction targeted Asp-929 in the third WHEP domain, therebyseparating the two synthetases. Using a neoepitope antibodydirected against the newly exposed C terminus, we demonstrateEPRS cleavage at Asp-929 in vitro and in vivo. Biochemical andbiophysical characterizations of the N-terminally generatedEPRS proteoform containing the glutamyl-tRNA synthetaseand most of the linker, including two WHEP domains, com-bined with structural analysis by small-angle neutron scattering,revealed a role for the WHEP domains in modulating conforma-tions of the catalytic core and GSH–S-transferase–C-terminal-like (GST-C) domain. WHEP-driven conformational rearrange-ment altered GST–C domain interactions and conferreddistinct oligomeric states in solution. Collectively, our resultsreveal long-range conformational changes imposed by theWHEP domains and illustrate how noncatalytic domains canmodulate the global structure of tRNA synthetases in complexeukaryotic systems.
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000856721 65017 $$0V:(DE-MLZ)GC-1602-2016$$2V:(DE-HGF)$$aPolymers, Soft Nano Particles and  Proteins$$x0
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000856721 7001_ $$0P:(DE-HGF)0$$aGogonea, Valentin$$b1
000856721 7001_ $$0P:(DE-HGF)0$$aDiDonato, Joseph A.$$b2
000856721 7001_ $$0P:(DE-Juel1)130893$$aPipich, Vitaliy$$b3
000856721 7001_ $$0P:(DE-HGF)0$$aYao, Peng$$b4
000856721 7001_ $$0P:(DE-HGF)0$$aChina, Arnab$$b5
000856721 7001_ $$0P:(DE-HGF)0$$aTopbas, Celalettin$$b6
000856721 7001_ $$00000-0002-7608-7566$$aVasu, Kommireddy$$b7
000856721 7001_ $$0P:(DE-HGF)0$$aArif, Abul$$b8
000856721 7001_ $$00000-0001-7124-6639$$aHazen, Stanley L.$$b9
000856721 7001_ $$0P:(DE-HGF)0$$aFox, Paul L.$$b10$$eCorresponding author
000856721 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.M117.807503$$gVol. 293, no. 23, p. 8843 - 8860$$n23$$p8843 - 8860$$tThe journal of biological chemistry$$v293$$x1083-351X$$y2018
000856721 8564_ $$uhttps://juser.fz-juelich.de/record/856721/files/J.%20Biol.%20Chem.-2018-Halawani-8843-60.pdf$$yPublished on 2018-04-11. Available in OpenAccess from 2019-04-11.
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