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@ARTICLE{Halawani:856721,
      author       = {Halawani, Dalia and Gogonea, Valentin and DiDonato, Joseph
                      A. and Pipich, Vitaliy and Yao, Peng and China, Arnab and
                      Topbas, Celalettin and Vasu, Kommireddy and Arif, Abul and
                      Hazen, Stanley L. and Fox, Paul L.},
      title        = {{S}tructural control of caspase-generated glutamyl-t{RNA}
                      synthetase by appended noncatalytic {WHEP} domains},
      journal      = {The journal of biological chemistry},
      volume       = {293},
      number       = {23},
      issn         = {1083-351X},
      address      = {Bethesda, Md.},
      publisher    = {Soc.72889},
      reportid     = {FZJ-2018-06072},
      pages        = {8843 - 8860},
      year         = {2018},
      abstract     = {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.},
      cin          = {JCNS-FRM-II / Neutronenstreuung ; JCNS-1},
      ddc          = {540},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
                      I:(DE-Juel1)JCNS-1-20110106},
      pnm          = {6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623)
                      / 6G15 - FRM II / MLZ (POF3-6G15)},
      pid          = {G:(DE-HGF)POF3-6G4 / G:(DE-HGF)POF3-6G15},
      experiment   = {EXP:(DE-MLZ)KWS1-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29643180},
      UT           = {WOS:000434941900010},
      doi          = {10.1074/jbc.M117.807503},
      url          = {https://juser.fz-juelich.de/record/856721},
}