View source for 7nzm


==Cryo-EM structure of pre-dephosphorylation complex of phosphorylated eIF2alpha with trapped holophosphatase (PP1A_D64A/PPP1R15A/G-actin/DNase I)==
<StructureSection load='7nzm' size='340' side='right'caption='[[7nzm]], [[Resolution|resolution]] 3.96&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7nzm]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NZM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NZM FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.96&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nzm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nzm OCA], [https://pdbe.org/7nzm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nzm RCSB], [https://www.ebi.ac.uk/pdbsum/7nzm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nzm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IF2A_HUMAN IF2A_HUMAN] Functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S preinitiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B.
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== Publication Abstract from PubMed ==
Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c-PPP1R15A-G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2alpha (eIF2alpha). G-actin, whose essential role in eIF2alpha dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2alpha to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2alpha kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.

Higher-order phosphatase-substrate contacts terminate the integrated stress response.,Yan Y, Harding HP, Ron D Nat Struct Mol Biol. 2021 Oct;28(10):835-846. doi: 10.1038/s41594-021-00666-7. , Epub 2021 Oct 8. PMID:34625748<ref>PMID:34625748</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7nzm" style="background-color:#fffaf0;"></div>

==See Also==
*[[Maltose-binding protein 3D structures|Maltose-binding protein 3D structures]]
*[[Protein phosphatase 3D structures|Protein phosphatase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Escherichia coli K-12]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Oryctolagus cuniculus]]
[[Category: Hardwick S]]
[[Category: Ron D]]
[[Category: Yan Y]]