期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 30, 期 21, 页码 5218-5233出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00265-10
关键词
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资金
- NIH
Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor (GEF) for eukaryotic translation initiation factor 2, which stimulates formation of the eIF2-GTP-Met-tRNA(i)(Met) ternary complex (TC) in a manner inhibited by phosphorylated eIF2 [eIF2(alpha P)]. While eIF2B contains five subunits, the epsilon/Gcd6 subunit is sufficient for GEF activity in vitro. The delta/Gcd2 and beta/Gcd7 subunits function with alpha/Gcn3 in the eIF2B regulatory subcomplex that mediates tight, inhibitory binding of eIF2(alpha P)-GDP, but the essential functions of delta/Gcd2 and beta/Gcd7 are not well understood. We show that the depletion of wild-type beta/Gcd7, three lethal beta/Gcd7 amino acid substitutions, and a synthetically lethal combination of substitutions in beta/Gcd7 and eIF2 alpha all impair eIF2 binding to eIF2B without reducing epsilon/Gcd6 abundance in the native eIF2B-eIF2 holo-complex. Additionally, beta/Gcd7 mutations that impair eIF2B function display extensive allele-specific interactions with mutations in the S1 domain of eIF2 alpha (harboring the phosphorylation site), which binds to eIF2B directly. Consistent with this, beta/Gcd7 can overcome the toxicity of eIF2(alpha P) and rescue native eIF2B function when overexpressed with delta/Gcd2 or gamma/Gcd1. In aggregate, these findings provide compelling evidence that beta/Gcd7 is crucial for binding of substrate by eIF2B in vivo, beyond its dispensable regulatory role in the inhibition of eIF2B by eIF (alpha P).
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