9rhh: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 9rhh is ~~ON HOLD~~

==Crystal structure of Kinase domain of HRI kinase==

~~Authors~~: ~~Rajasekaran~~, M.B., ~~Roe~~, S.M., ~~Spencer~~, J.

== Structural highlights ==

<table><tr><td colspan='2'>[[9rhh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9RHH OCA]. For a guided tour on the structure components use [https://proteopedia.org/fgij/fg.htm?mol=9RHH FirstGlance].

~~Description~~: ~~Crystal structure~~ of ~~Kinase domain~~ of HRI kinase

</td></tr><tr id='method'><td class="sblockLbl">[[Empirical_models|Method:]]</td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.08Å</td></tr>

[[Category: ~~Unreleased~~ Structures]]

<tr id='ligand'><td class="sblockLbl">[[Ligand|Ligands:]]</td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>

[[Category: ~~Roe, S.M~~]]

<tr id='resources'><td class="sblockLbl">Resources:</td><td class="sblockDat">[https://proteopedia.org/fgij/fg.htm?mol=9rhh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9rhh OCA], [https://pdbe.org/9rhh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9rhh RCSB], [https://www.ebi.ac.uk/pdbsum/9rhh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9rhh ProSAT]</td></tr>

[[Category: ~~Spencer, J~~]]

</table>

[[Category: ~~Rajasekaran, M.B~~]]

== Disease ==

[https://www.uniprot.org/uniprot/E2AK1_HUMAN E2AK1_HUMAN] The disease may be caused by variants affecting the gene represented in this entry.

== Function ==

[https://www.uniprot.org/uniprot/E2AK1_HUMAN E2AK1_HUMAN] Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707, PubMed:37327776). Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (By similarity). This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR (By similarity). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (By similarity). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (By similarity). Iron deficiency also triggers activation by full-length DELE1 (PubMed:37327776). Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707). Also acts as an activator of mitophagy in response to mitochondrial damage: catalyzes phosphorylation of eIF-2-alpha (EIF2S1) following activation by S-DELE1, thereby promoting mitochondrial localization of EIF2S1, triggering PRKN-independent mitophagy (PubMed:38340717).[UniProtKB:Q9Z2R9]<ref>PMID:32132706</ref> <ref>PMID:32132707</ref> <ref>PMID:32197074</ref> <ref>PMID:37550454</ref> <ref>PMID:38340717</ref>

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Rajasekaran MB]]

[[Category: Roe SM]]

[[Category: Spencer J]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9rhh is ON HOLD
+==Crystal structure of Kinase domain of HRI kinase==
+<StructureSection load='9rhh' size='340' side='right'caption='[[9rhh]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
-Authors: Rajasekaran, M.B., Roe, S.M., Spencer, J.
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9rhh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9RHH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9RHH FirstGlance]. <br>
-Description: Crystal structure of Kinase domain of HRI kinase
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.08&#8491;</td></tr>
-[[Category: Unreleased Structures]]
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
-[[Category: Roe, S.M]]
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9rhh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9rhh OCA], [https://pdbe.org/9rhh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9rhh RCSB], [https://www.ebi.ac.uk/pdbsum/9rhh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9rhh ProSAT]</span></td></tr>
-[[Category: Spencer, J]]
+</table>
-[[Category: Rajasekaran, M.B]]
+== Disease ==
+[https://www.uniprot.org/uniprot/E2AK1_HUMAN E2AK1_HUMAN] The disease may be caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/E2AK1_HUMAN E2AK1_HUMAN] Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:38340717). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707, PubMed:37327776). Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity (By similarity). This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR (By similarity). Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions (By similarity). In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties (By similarity). It thereby plays an essential protective role for RBC survival in anemias of iron deficiency (By similarity). Iron deficiency also triggers activation by full-length DELE1 (PubMed:37327776). Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (PubMed:32132706, PubMed:32132707). Also acts as an activator of mitophagy in response to mitochondrial damage: catalyzes phosphorylation of eIF-2-alpha (EIF2S1) following activation by S-DELE1, thereby promoting mitochondrial localization of EIF2S1, triggering PRKN-independent mitophagy (PubMed:38340717).[UniProtKB:Q9Z2R9]<ref>PMID:32132706</ref> <ref>PMID:32132707</ref> <ref>PMID:32197074</ref> <ref>PMID:37550454</ref> <ref>PMID:38340717</ref>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Rajasekaran MB]]
+[[Category: Roe SM]]
+[[Category: Spencer J]]