ライフサイエンスコーパス: eIF2B

1 eIF2B acts as a guanine nucleotide exchange factor (GEF)

2 eIF2B controls the recruitment of the initiator methiony

3 eIF2B facilitates and controls protein synthesis in euka

4 eIF2B is a five-subunit guanine nucleotide exchange fact

5 eIF2B is a heteropentameric guanine-nucleotide exchange

6 eIF2B is an essential multi-subunit factor and a major t

7 eIF2B is comprised of catalytic and regulatory subcomple

8 eIF2B is the heteropentameric guanine nucleotide exchang

9 eIF2B is unusually complex with five subunits (alpha-eps

10 eIF2B mutations predominantly affect the brain white mat

11 eIF2B(alphabetagammadeltaepsilon)2 decamers show greater

12 eIF2B, the nucleotide exchange factor for eIF2, is a het

13 eIF2B-related disorders have a clinical spectrum ranging

14 eukaryotic translation initiation factor 2B (eIF2B) and the very-long-chain fatty acid (VLCFA) synthe

15 bunits of eukaryocytic initiation factor 2B (eIF2B) are the cause of vanishing white-matter disease/c

16 Eukaryotic translation initiation factor 2B (eIF2B) is a five-subunit complex that catalyzes guanine

17 Eukaryotic translation initiation factor 2B (eIF2B) is a heteropentameric guanine nucleotide exchange

18 Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor (GEF) f

19 Eukaryotic initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor for eIF

20 Eukaryotic translation initiation factor 2B (eIF2B) is the heteropentameric guanine nucleotide exchan

21 Eukaryotic initiation factor 2B (eIF2B) plays a key role in protein synthesis and in its

22 eukaryotic translation initiation factor 2B (eIF2B) provides a fundamental controlled point in the pa

23 Eukaryotic initiation factor 2B (eIF2B), a five-subunit guanine nucleotide exchange facto

24 K-3beta is translation initiation factor 2B (eIF2B), linking global regulation of protein synthesis t

25 tations in translation initiation factor 2B (eIF2B).

26 eukaryotic translation initiation factor 2B (eIF2B).

27 eukaryotic translation initiation factor 2B (eIF2B).

28 ced hypertrophy does not depend on GSK-3beta/eIF2B signaling.

29 ow ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (delta-subunit) co

30 or amino acids, insulin no longer activates eIF2B.

31 s, suggesting that these substitutions allow eIF2B to accept phosphorylated eIF2 as a substrate for n

32 2, around the phosphorylation site, allowing eIF2B to detect and respond to phosphoserine at residue

33 contrast, the GCD1 and GCD6 subunits form an eIF2B subcomplex that binds equally to eIF2 and eIF2(alp

34 Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity.

35 g an affinity-binding assay, we show that an eIF2B subcomplex of the GCN3, GCD7, and GCD2 subunits bi

36 ons of eIF2B(alphabetagammadeltaepsilon) and eIF2B(betagammadeltaepsilon) complexes, with important i

37 Cross-links between eIF2 and eIF2B allow modelling of interactions that contribute to

38 SRIB targets an interaction between eIF2 and eIF2B that lies at the core of the ISR.

39 for structural interactions between eIF2 and eIF2B that promote wild-type rates of nucleotide exchang

40 n(s) of eIF2 in the absence of eIF2alpha and eIF2B and are consistent with the idea that the latter f

41 he delta- and epsilon-subunits of eIF2B, and eIF2B was shown to bind only to the beta-subunit of eIF2

42 Dual and reciprocal modulation of eIF4F and eIF2B was leucine-specific because isoleucine, a structu

43 mediate the binding of eIF2 to both eIF5 and eIF2B.

44 egulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2alpha phosphor

45 dissociation inhibitor (GDI) functions, and eIF2B is the guanine nucleotide exchange factor (GEF).

46 tors of eIF2 function, eIF2alpha kinases and eIF2B, have evolved to recognize the same surface and ov

47 alterations in global protein synthesis and eIF2B activity were maintained in the presence of the ho

48 eraction is specifically between YBR159W and eIF2B and not between other members of the translation i

49 oplasmic reservoir for eIF2 that antagonizes eIF2B-promoted guanine nucleotide exchange, enabling coo

50 alpha subunit of eIF2 directly contacts any eIF2B subunits or whether this interaction is modulated

51 e to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIF2alpha, suggesting

52 These data uncover competition between eIF2B and eIF5 for TC and identify that phosphorylated e

53 itical for interprotein interactions between eIF2B subunits necessary for eIF2B complex formation.

54 pose a model for domain interactions between eIF2B subunits.

55 serine-51, inhibiting nucleotide exchange by eIF2B.

56 n intermediate complexes can be inhibited by eIF2B.

57 /Gcd7 is crucial for binding of substrate by eIF2B in vivo, beyond its dispensable regulatory role in

58 terestingly, the same conditions that bypass eIF2B also overcome the requirement for the normally ess

59 Consistent with bypassing eIF2B, these conditions also suppress the lethal effect

60 e identification of regulatory and catalytic eIF2B subcomplexes leads us to propose that binding of e

61 th null mutations in the VLCFA pathway cause eIF2B to appear as numerous foci throughout the cytoplas

62 ated eIF2 [eIF2(alphaP)] and to characterize eIF2B regulatory mutations that render translation initi

63 unphosphorylated eIF2, eIF5 can out-compete eIF2B to stabilize TC/eIF5 complexes.

64 In contrast, eIF2B activity remained unchanged in response to AICAR t

65 In contrast, eIF2B lacking the alpha-subunit is insensitive to inhibi

66 unknown, regulatory mechanisms that control eIF2B activity.

67 TC/eIF5 is formed with phosphorylated eIF2, eIF2B outcompetes eIF5 and destabilizes TC.

68 Unlike wild-type eIF2B, eIF2B complexes with mutated GCN3 or GCD7 subunits effic

69 ment with this, archaea appear to lack eIF5, eIF2B and the lysine-rich binding domain for these facto

70 No differences were noted with either eIF2B or eIF2 alpha.

71 protein synthesis initiation in eukaryotes, eIF2B is the guanine-nucleotide exchange factor for eIF2

72 5 and the guanine-nucleotide exchange factor eIF2B modulate eIF2 function through direct interactions

73 ty of the guanine nucleotide-exchange factor eIF2B.

74 e GTP form by the nucleotide exchange factor eIF2B.

75 CREB) protein, translation-initiation factor eIF2B, and the nucleolar p53-interacting protein nucleos

76 inhibition of translation initiation factor eIF2B.

77 ge activity of translation initiation factor eIF2B.

78 the activity of eukaryotic initiation factor eIF2B.

79 whereas eIF2.GDP binds the pentameric factor eIF2B for guanine nucleotide exchange.

80 on AUG codon recognition, whereas the factor eIF2B promotes guanine nucleotide exchange on eIF2 to re

81 ely the sugar isomerases, translation factor eIF2B, ligand-binding domains of the DeoR-family transcr

82 ion with guanine nucleotide exchange factor (eIF2B) are described.

83 r of its guanine nucleotide exchange factor, eIF2B, impairing formation of the ternary complex and th

84 with the guanine nucleotide exchange factor, eIF2B, is a key mechanism for controlling translation un

85 r of its guanine nucleotide exchange factor, eIF2B.

86 P by the complex nucleotide exchange factor, eIF2B.

87 bits its guanine nucleotide exchange factor, eIF2B.

88 the activity of eIF2 are translation factors eIF2B and eIF5, thought to primarily function with eIF2-

89 ast to other translation initiation factors, eIF2B and eIF2 colocalize to a specific cytoplasmic locu

90 First, eIF2B GDF is insensitive to eIF2alpha phosphorylation, u

91 on with its substrate, eIF2, in vivo and for eIF2B activity in vitro.

92 Mutations in the genes for eIF2B cause an often severe neurological disorder, "vani

93 actions between eIF2B subunits necessary for eIF2B complex formation.

94 initiator tRNA, overcome the requirement for eIF2B in vivo.

95 eract with the eIF2 complex, a requisite for eIF2B inhibition by eIF2alpha phosphorylation.

96 toxicity, presumably by titrating GCN3 from eIF2B and producing the four-subunit form of eIF2B that

97 cluding GCN3, the nonessential subunit, from eIF2B; thus, all three proteins are critical for regulat

98 of guanine nucleotide exchange factor (GEF) eIF2B.

99 the guanine-nucleotide exchange factor (GEF) eIF2B.

100 ts guanine nucleotide exchange factor (GEF), eIF2B.

101 with the eIF2 guanine exchange factor (GEF), eIF2B.

102 terized 29 novel mutations in the homologous eIF2B subunits encoded by GCD2, GCD7, and GCN3 that redu

103 dditionally, beta/Gcd7 mutations that impair eIF2B function display extensive allele-specific interac

104 Notably, impaired eIF2B activity induced by PERK activation in oligodendro

105 point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pa

106 rylating eIF2alpha, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutat

107 eIF5 and TC/eIF5 complexes, thereby impeding eIF2B reaction and MFC formation, respectively.

108 The changes in eIF2B activity could be explained in part by modulation

109 possibly due to the occurrence of defects in eIF2B that overcome the inhibitory effects of eIF2alpha

110 that these segments form a single domain in eIF2B that makes multiple contacts with the alpha subuni

111 lf of GCD2 comprise the regulatory domain in eIF2B.

112 GCD7, and GCN3 perform related functions in eIF2B regulation.

113 In addition, inherited mutations in eIF2B cause a fatal leukoencephalopathy.

114 of eIF2alpha and a concomitant reduction in eIF2B activity in perfused livers from wild-type mice, b

115 Gcn2p phosphorylates eIF2 to inhibit eIF2B.

116 In eukaryotic translation initiation, eIF2B is the guanine nucleotide exchange factor (GEF) re

117 It was shown previously that the largest eIF2B subunit, eIF2Bepsilon, is the only single subunit

118 F2B function by mutation and in fact lowered eIF2B activity in strains lacking eIF2(alphaP).

119 t, catalytic, subunit (epsilon) of mammalian eIF2B.

120 ed the subunit interactions within mammalian eIF2B by using a combination of mass spectrometry and in

121 By modulating eIF2B function, ISRIB promises to be an invaluable tool

122 d prevents the latter from inhibiting native eIF2B.

123 e toxicity of eIF2(alphaP) and rescue native eIF2B function when overexpressed with delta/Gcd2 or gam

124 educing epsilon/Gcd6 abundance in the native eIF2B-eIF2 holocomplex.

125 Expression of nonphosphorylatable eIF2B prevented cytochrome c release resulting from PI 3

126 survival, expression of nonphosphorylatable eIF2B prevented inhibition of protein synthesis followin

127 with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5).

128 We now report that ISRIB is an activator of eIF2B.

129 The guanine nucleotide exchange activity of eIF2B plays a key regulatory role in the translation ini

130 the guanine nucleotide exchange activity of eIF2B, whereas phosphorylation by casein kinase II or pr

131 using an increase in the binding affinity of eIF2B for eIF2.

132 it did cause an increase in the affinity of eIF2B for eIF2.

133 However, steady-state kinetic analysis of eIF2B-catalyzed nucleotide exchange revealed that the ab

134 er51 phosphorylation impaired the binding of eIF2B to phosphorylated eIF2alpha.

135 a-subunit of eIF2 did not promote binding of eIF2B to the isolated subunit.

136 ts implicate a defined cytoplasmic center of eIF2B in the exchange of guanine nucleotides on the eIF2

137 he first structural model for the complex of eIF2B with its substrate, eIF2-GDP, reaction intermediat

138 Since control of eIF2B is independent of mTOR, these data indicate the op

139 cial for full activity and proper control of eIF2B.

140 A focused core of eIF2B guanine nucleotide exchange might allow either gre

141 that eIF2B is actually decameric, a dimer of eIF2B(betagammadeltaepsilon) tetramers stabilized by 2 c

142 together constitute the catalytic domain of eIF2B.

143 Dysregulation of eIF2B activity is associated with a number of pathologie

144 eIF5 GDI complex and determine the effect of eIF2B on this release.

145 We demonstrate that expression of eIF2B mutants lacking the GSK-3beta phosphorylation or p

146 eIF2B and producing the four-subunit form of eIF2B that is less sensitive to eIF2(alphaP).

147 otal role for eIF2Bdelta in the formation of eIF2B(betagammadeltaepsilon) tetramers.

148 Both the five- and four-subunit forms of eIF2B exhibit similar rates of guanine nucleotide exchan

149 ionation experiments show that a fraction of eIF2B cofractionates with lipid membranes in a YBR159W-i

150 the guanine nucleotide exchange function of eIF2B all inhibit eIF2 shuttling into the foci.

151 2, gcd11-K250R, which mimics the function of eIF2B in vitro.

152 ; however, it did suppress the impairment of eIF2B caused by the gcn3c-R104K mutation.

153 The inactivation of eIF2B not only suppresses the initiation of protein tran

154 nd GCN3 that reduce or abolish inhibition of eIF2B activity by eIF2 phosphorylated on its alpha subun

155 (i) a novel mechanism for the inhibition of eIF2B activity, whereby eIF2alpha phosphorylation destab

156 eIF2(alphaP) and mediates the inhibition of eIF2B activity.

157 Since we show that inhibition of eIF2B also drives neural crest migration and yeast invas

158 subcomplex is crucial for the inhibition of eIF2B and attendant downregulation of protein synthesis

159 ensable regulatory role in the inhibition of eIF2B by eIF (alphaP).

160 y subunit GCD7 that eliminated inhibition of eIF2B by eIF2(alphaP) also impaired binding of phosphory

161 the protein into a competitive inhibitor of eIF2B by causing an increase in the binding affinity of

162 onverts eIF2 into a competitive inhibitor of eIF2B, which triggers the integrated stress response (IS

163 F2 x GDP from a substrate to an inhibitor of eIF2B.

164 sis, we have investigated the involvement of eIF2B, which is inhibited as a result of GSK-3beta phosp

165 We examined the levels of eIF2B subunits in a panel of different mouse tissues and

166 e tissues and identified different levels of eIF2B subunits, particularly eIF2Balpha, which implies h

167 obably because they contain higher levels of eIF2B, the initiation factor that is inhibited by eIF2al

168 MS and cross-linking of eIF2B complexes allows us to propose a model for the sub

169 subcomplex did not compensate for a loss of eIF2B function by mutation and in fact lowered eIF2B act

170 hermodynamics to elucidate the mechanisms of eIF2B action and its regulation by phosphorylation of th

171 arch, the underlying molecular mechanisms of eIF2B action and regulation remain unknown.

172 obal protein synthesis through modulation of eIF2B activity.

173 ranslation resulting from phosphorylation of eIF2B by GSK-3beta thus appears to contribute to the con

174 of 43.2 pmol of GDP released per min/pmol of eIF2B at 30 degrees C is approximately 1 order of magnit

175 heterogeneity in the cellular proportions of eIF2B(alphabetagammadeltaepsilon) and eIF2B(betagammadel

176 hree proteins are critical for regulation of eIF2B by eIF2(alphaP).

177 advances in the understanding of the role of eIF2B as a cause of a common leukodystrophy syndrome.

178 ted eIF2alpha interacts with a subcomplex of eIF2B formed by the three regulatory subunits alpha/GCN3

179 ouble point mutation in the delta-subunit of eIF2B has been identified that results in insensitivity

180 directly to eIF5 and the epsilon subunit of eIF2B, and we map the interaction sites to the catalytic

181 eIF5 and the catalytic (epsilon) subunit of eIF2B.

182 activity of the catalytic epsilon-subunit of eIF2B.

183 mutations in the beta and delta subunits of eIF2B (encoded by GCD7 and GCD2, respectively).

184 idence that the alpha- and delta-subunits of eIF2B are involved in mediating the effect of substrate

185 ate the alpha-, beta-, and delta-subunits of eIF2B in mediating the inhibition by substrate phosphory

186 r the isolated delta- or epsilon-subunits of eIF2B was shown to be located within approximately 70 am

187 d only to the delta- and epsilon-subunits of eIF2B, and eIF2B was shown to bind only to the beta-subu

188 gs of the alpha, beta, and delta subunits of eIF2B.

189 ion of the ISR and its stimulatory effect on eIF2B GEF activity toward its substrate, the translation

190 ilon (eIF2Bepsilon being the catalytic one), eIF2B has always been considered an alphabetagammadeltae

191 as been reported to directly bind to eIF5 or eIF2B.

192 rred independent of similar changes in other eIF2B subunits.

193 eIF2Bvarepsilon mutations, but not other eIF2B mutations, enhance the ability of overexpressed eI

194 truncated GCD2 protein interacted with other eIF2B subunits only when GCD7 and GCN3 were overexpresse

195 We propose a new model to place eIF2B GDF function in the context of efficient eIF2 recy

196 e show that the catalytic domain can provide eIF2B biological function in vivo when elevated levels e

197 we have coexpressed the five subunits of rat eIF2B in Sf9 cells using the baculovirus system and have

198 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation.

199 This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 target

200 ession of a specific isoform of a regulatory eIF2B subunit, eIF2Bdelta variant 1 (V1).

201 ubunit of eIF2 (eIF2alpha), which sequesters eIF2B to prevent exchange activity.

202 at a faster rate compared with five-subunit eIF2B.

203 e also expressed and purified a four-subunit eIF2B complex lacking the alpha-subunit.

204 igodendrocytes during development suppressed eIF2B activity and reproduced the characteristic feature

205 provide evidence that fusel alcohols target eIF2B in order to bring about translational regulation.

206 Although it is generally accepted that eIF2B is a pentamer of five non-identical subunits (alph

207 h with purified proteins we demonstrate that eIF2B binds to eIF2 with equal affinity irrespective of

208 We demonstrate that eIF2B has a second activity as a GDI displacement factor

209 ion of alpha-actin and SM22, indicating that eIF2B is required for GSK-3beta-mediated airway smooth m

210 Our data reveal that eIF2B is actually decameric, a dimer of eIF2B(betagammad

211 We show that eIF2B can compete with Met-tRNAi for eIF2-GTP and can de

212 subunits (alpha-epsilon), here we show that eIF2B is a decamer.

213 The binding site on eIF2beta for either the eIF2B holoprotein, or the isolated delta- or epsilon-sub

214 roduct, TC, with direct implications for the eIF2B catalytic mechanism.

215 All five sites are phosphorylated in the eIF2B complex in vivo.

216 in the interactions between subunits in the eIF2B complex.

217 cd7 subunits function with alpha/Gcn3 in the eIF2B regulatory subcomplex that mediates tight, inhibit

218 Mutations in SUI2 and in the eIF2B regulatory subunit GCD7 that eliminated inhibition

219 eIF2alpha phosphorylation inactivates the eIF2B complex.

220 (alphaP) can be decreased by deletion of the eIF2B alpha subunit (encoded by GCN3) and by point mutat

221 tory interaction prevents association of the eIF2B catalytic subcomplex with the beta and gamma subun

222 dulation of the phosphorylation state of the eIF2B epsilon-subunit, because deprivation of either ami

223 Gcd1p forms part of the eIF2B guanine nucleotide complex that is responsible for

224 n aIF2B was used to construct a model of the eIF2B regulatory subcomplex.

225 rts eIF2 into a competitive inhibitor of the eIF2B-catalyzed exchange reaction.

226 he extension of the clinical features of the eIF2B-related disorders to encompass both infant- and ad

227 hione S-transferase [GST]-SUI2) bound to the eIF2B regulatory subcomplex in vitro, in a manner stimul

228 tight binding of phosphorylated SUI2 to the eIF2B regulatory subcomplex is crucial for the inhibitio

229 eIF2(alphaP) holoprotein for binding to the eIF2B regulatory subcomplex.

230 ed binding of phosphorylated GST-SUI2 to the eIF2B regulatory subunits.

231 for achieving correct stoichiometry of these eIF2B subunits in the cell.

232 d sites of regulatory mutations in the three eIF2B subunits in yeast are juxtaposed in one continuous

233 40S ribosomal subunit were assessed through eIF2B activity and eIF2 alpha phosphorylation on Ser-51.

234 Thus, eIF2B-catalyzed TC formation appears to be fine-tuned by

235 cd7 and eIF2alpha all impair eIF2 binding to eIF2B without reducing epsilon/Gcd6 abundance in the nat

236 t of eIF2 is directly involved in binding to eIF2B.

237 ng the phosphorylation site), which binds to eIF2B directly.

238 ecamers show greater binding to eIF2 than to eIF2B(betagammadeltaepsilon) tetramers, which may underl

239 nucleotide-exchange activity than wild-type eIF2B that is not inhibited by eIF2(alphaP).

240 Unlike wild-type eIF2B, eIF2B complexes with mutated GCN3 or GCD7 subunit

241 was very rapid and no longer dependent upon eIF2B.

242 Indeed eIF2 shuttles into these foci whereas eIF2B remains largely resident.

243 While eIF2B contains five subunits, the epsilon/Gcd6 subunit i

244 complex (MFC), while eIF2GDP associates with eIF2B for guanine nucleotide exchange.

245 ence that aIF2B has functions in common with eIF2B, the crystal structure established for an aIF2B wa

246 a model for the subunit arrangements within eIF2B where the subunit assembly occurs through catalyti

247 ubunit stoichiometry and interactions within eIF2B and eIF2.

248 In support of this model, our yeast eIF2B preparations bind guanine nucleotides, with an app

249 We have purified yeast eIF2B and characterized its catalytic properties in vitr

250 -exchange assay to show that wild-type yeast eIF2B is inhibited by phosphorylated eIF2 [eIF2(alphaP)]