RRC ID 58308
Author Kashiwagi K, Yokoyama T, Nishimoto M, Takahashi M, Sakamoto A, Yonemochi M, Shirouzu M, Ito T.
Title Structural basis for eIF2B inhibition in integrated stress response.
Journal Science
Abstract A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers the methionylated initiator tRNA to the ribosome in a guanosine 5'-triphosphate-dependent manner. By contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor, eIF2B. To elucidate how the eIF2 phosphorylation status regulates the eIF2B activity, we determined cryo-electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. These structures explain how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B.
Volume 364(6439)
Pages 495-499
Published 2019-5-3
DOI 10.1126/science.aaw4104
PII 364/6439/495
PMID 31048492
MeSH Amino Acid Motifs Cryoelectron Microscopy Eukaryotic Initiation Factor-2 / chemistry* Eukaryotic Initiation Factor-2B / antagonists & inhibitors* Eukaryotic Initiation Factor-2B / chemistry* Eukaryotic Initiation Factor-2B / metabolism Humans Phosphorylation Stress, Physiological*
IF 41.846
Times Cited 12
DNA material pET28-3C-eIF2Ba (RDB17722) pETDuet-eIF2Bd-eIF2Bb (RDB17723) pCOLA-3C-eIF2Be-eIF2Bg (RDB17724) pEBMulti-Neo-human-eIF2alpha (RDB17725) pEBMulti-Neo-human-eIF2beta (RDB17726) pEBMulti-Neo-human-eIF2gamma-FlagHis8 (RDB17727) pEBMulti-Neo-human-CDC123 (RDB17728)