TY  - JOUR
AU  - Halawani, Dalia
AU  - Gogonea, Valentin
AU  - DiDonato, Joseph A.
AU  - Pipich, Vitaliy
AU  - Yao, Peng
AU  - China, Arnab
AU  - Topbas, Celalettin
AU  - Vasu, Kommireddy
AU  - Arif, Abul
AU  - Hazen, Stanley L.
AU  - Fox, Paul L.
TI  - Structural control of caspase-generated glutamyl-tRNA synthetase by appended noncatalytic WHEP domains
JO  - The journal of biological chemistry
VL  - 293
IS  - 23
SN  - 1083-351X
CY  - Bethesda, Md.
PB  - Soc.72889
M1  - FZJ-2018-06072
SP  - 8843 - 8860
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29643180
UR  - <Go to ISI:>//WOS:000434941900010
DO  - DOI:10.1074/jbc.M117.807503
UR  - https://juser.fz-juelich.de/record/856721
ER  -