Structural basis for eIF2B inhibition in integrated stress response
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 rib...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2019-05, Vol.364 (6439), p.495-499 |
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| creator | Kashiwagi, Kazuhiro Yokoyama, Takeshi Nishimoto, Madoka Takahashi, Mari Sakamoto, Ayako Yonemochi, Mayumi Shirouzu, Mikako Ito, Takuhiro |
| description | 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. |
| doi_str_mv | 10.1126/science.aaw4104 |
| format | Article |
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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.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aaw4104</identifier><identifier>PMID: 31048492</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Brain ; Cellular stress response ; Crystal structure ; Crystallography ; Electron microscopy ; Eukaryotes ; Exchanging ; Gene expression ; Guanine ; Guanine nucleotide exchange factor ; Guanosine ; Head injuries ; Initiation factor eIF-2 ; Kinases ; Locks ; Microscopy ; Neurodegenerative diseases ; Neurological diseases ; Phosphorylation ; Protein biosynthesis ; Protein synthesis ; Stimuli ; Stress ; Stress response ; Therapeutic applications ; Translation ; Traumatic brain injury ; tRNA</subject><ispartof>Science (American Association for the Advancement of Science), 2019-05, Vol.364 (6439), p.495-499</ispartof><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3694-cfca4475d33363aac19f6521d4342b4d82ae33ae0382a79291d2183f238097ed3</citedby><cites>FETCH-LOGICAL-c3694-cfca4475d33363aac19f6521d4342b4d82ae33ae0382a79291d2183f238097ed3</cites><orcidid>0000-0002-0299-9140 ; 0000-0003-3704-5205 ; 0000-0001-6470-5817 ; 0000-0002-7997-2149</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2870,2871,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31048492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kashiwagi, Kazuhiro</creatorcontrib><creatorcontrib>Yokoyama, Takeshi</creatorcontrib><creatorcontrib>Nishimoto, Madoka</creatorcontrib><creatorcontrib>Takahashi, Mari</creatorcontrib><creatorcontrib>Sakamoto, Ayako</creatorcontrib><creatorcontrib>Yonemochi, Mayumi</creatorcontrib><creatorcontrib>Shirouzu, Mikako</creatorcontrib><creatorcontrib>Ito, Takuhiro</creatorcontrib><title>Structural basis for eIF2B inhibition in integrated stress response</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>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.</description><subject>Brain</subject><subject>Cellular stress response</subject><subject>Crystal structure</subject><subject>Crystallography</subject><subject>Electron microscopy</subject><subject>Eukaryotes</subject><subject>Exchanging</subject><subject>Gene expression</subject><subject>Guanine</subject><subject>Guanine nucleotide exchange factor</subject><subject>Guanosine</subject><subject>Head injuries</subject><subject>Initiation factor eIF-2</subject><subject>Kinases</subject><subject>Locks</subject><subject>Microscopy</subject><subject>Neurodegenerative diseases</subject><subject>Neurological diseases</subject><subject>Phosphorylation</subject><subject>Protein biosynthesis</subject><subject>Protein synthesis</subject><subject>Stimuli</subject><subject>Stress</subject><subject>Stress response</subject><subject>Therapeutic 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basis for eIF2B inhibition in integrated stress response</title><author>Kashiwagi, Kazuhiro ; Yokoyama, Takeshi ; Nishimoto, Madoka ; Takahashi, Mari ; Sakamoto, Ayako ; Yonemochi, Mayumi ; Shirouzu, Mikako ; Ito, Takuhiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3694-cfca4475d33363aac19f6521d4342b4d82ae33ae0382a79291d2183f238097ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Brain</topic><topic>Cellular stress response</topic><topic>Crystal structure</topic><topic>Crystallography</topic><topic>Electron microscopy</topic><topic>Eukaryotes</topic><topic>Exchanging</topic><topic>Gene expression</topic><topic>Guanine</topic><topic>Guanine nucleotide exchange factor</topic><topic>Guanosine</topic><topic>Head injuries</topic><topic>Initiation factor eIF-2</topic><topic>Kinases</topic><topic>Locks</topic><topic>Microscopy</topic><topic>Neurodegenerative diseases</topic><topic>Neurological diseases</topic><topic>Phosphorylation</topic><topic>Protein biosynthesis</topic><topic>Protein synthesis</topic><topic>Stimuli</topic><topic>Stress</topic><topic>Stress response</topic><topic>Therapeutic applications</topic><topic>Translation</topic><topic>Traumatic brain injury</topic><topic>tRNA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kashiwagi, Kazuhiro</creatorcontrib><creatorcontrib>Yokoyama, Takeshi</creatorcontrib><creatorcontrib>Nishimoto, Madoka</creatorcontrib><creatorcontrib>Takahashi, Mari</creatorcontrib><creatorcontrib>Sakamoto, Ayako</creatorcontrib><creatorcontrib>Yonemochi, Mayumi</creatorcontrib><creatorcontrib>Shirouzu, Mikako</creatorcontrib><creatorcontrib>Ito, Takuhiro</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology 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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. 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| subjects | Brain Cellular stress response Crystal structure Crystallography Electron microscopy Eukaryotes Exchanging Gene expression Guanine Guanine nucleotide exchange factor Guanosine Head injuries Initiation factor eIF-2 Kinases Locks Microscopy Neurodegenerative diseases Neurological diseases Phosphorylation Protein biosynthesis Protein synthesis Stimuli Stress Stress response Therapeutic applications Translation Traumatic brain injury tRNA |
| title | Structural basis for eIF2B inhibition in integrated stress response |
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