%0 Journal Article
%A Halawani, Dalia
%A Gogonea, Valentin
%A DiDonato, Joseph A.
%A Pipich, Vitaliy
%A Yao, Peng
%A China, Arnab
%A Topbas, Celalettin
%A Vasu, Kommireddy
%A Arif, Abul
%A Hazen, Stanley L.
%A Fox, Paul L.
%T Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains
%J The journal of biological chemistry
%V 293
%N 23
%@ 1083-351X
%C Bethesda, Md.
%I Soc.72889
%M FZJ-2018-06072
%P 8843 - 8860
%D 2018
%X Aminoacyl-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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29643180
%U <Go to ISI:>//WOS:000434941900010
%R 10.1074/jbc.M117.807503
%U https://juser.fz-juelich.de/record/856721