7tts

From Proteopedia

(Difference between revisions)

Current revision

Skd3, hexamer, filtered

Structural highlights

7tts is a 7 chain structure with sequence from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.9Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CLPB_HUMAN Autosomal dominant severe congenital neutropenia;3-methylglutaconic aciduria type 7. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

CLPB_HUMAN Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins (PubMed:32573439, PubMed:34115842, PubMed:35247700, PubMed:36170828, PubMed:36745679). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117). Plays a role in granulocyte differentiation (PubMed:34115842).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with defective protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). How Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies.

, PMID:36170828^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yoshinaka T, Kosako H, Yoshizumi T, Furukawa R, Hirano Y, Kuge O, Tamada T, Koshiba T. Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region. iScience. 2019 Sep 27;19:1065-1078. doi: 10.1016/j.isci.2019.08.056. Epub 2019, Sep 3. PMID:31522117 doi:http://dx.doi.org/10.1016/j.isci.2019.08.056
↑ Cupo RR, Shorter J. Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations. Elife. 2020 Jun 23;9:e55279. PMID:32573439 doi:10.7554/eLife.55279
↑ Warren JT, Cupo RR, Wattanasirakul P, Spencer DH, Locke AE, Makaryan V, Bolyard AA, Kelley ML, Kingston NL, Shorter J, Bellanné-Chantelot C, Donadieu J, Dale DC, Link DC. Heterozygous variants of CLPB are a cause of severe congenital neutropenia. Blood. 2022 Feb 3;139(5):779-791. PMID:34115842 doi:10.1182/blood.2021010762
↑ Spaulding Z, Thevarajan I, Schrag LG, Zubcevic L, Zolkiewska A, Zolkiewski M. Human mitochondrial AAA+ ATPase SKD3/CLPB assembles into nucleotide-stabilized dodecamers. Biochem Biophys Res Commun. 2022 Apr 30;602:21-26. PMID:35247700 doi:10.1016/j.bbrc.2022.02.101
↑ Cupo RR, Rizo AN, Braun GA, Tse E, Chuang E, Gupta K, Southworth DR, Shorter J. Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3. Cell Rep. 2022 Sep 27;40(13):111408. PMID:36170828 doi:10.1016/j.celrep.2022.111408
↑ Wu D, Liu Y, Dai Y, Wang G, Lu G, Chen Y, Li N, Lin J, Gao N. Comprehensive structural characterization of the human AAA+ disaggregase CLPB in PLoS Biol. 2023 Feb 6;21(2):e3001987. PMID:36745679 doi:10.1371/journal.pbio.3001987
↑ Cupo RR, Rizo AN, Braun GA, Tse E, Chuang E, Gupta K, Southworth DR, Shorter J. Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3. Cell Rep. 2022 Sep 27;40(13):111408. PMID:36170828 doi:10.1016/j.celrep.2022.111408

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7tts"

Categories: Bos taurus | Homo sapiens | Large Structures | Cupo RR | Rizo AN

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7tts is ON HOLD
+==Skd3, hexamer, filtered==
+<StructureSection load='7tts' size='340' side='right'caption='[[7tts]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7tts]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TTS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TTS 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]] 2.9&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7tts FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tts OCA], [https://pdbe.org/7tts PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tts RCSB], [https://www.ebi.ac.uk/pdbsum/7tts PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tts ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/CLPB_HUMAN CLPB_HUMAN] Autosomal dominant severe congenital neutropenia;3-methylglutaconic aciduria type 7. The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/CLPB_HUMAN CLPB_HUMAN] Functions as a regulatory ATPase and participates in secretion/protein trafficking process. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins (PubMed:32573439, PubMed:34115842, PubMed:35247700, PubMed:36170828, PubMed:36745679). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117). Plays a role in granulocyte differentiation (PubMed:34115842).<ref>PMID:31522117</ref> <ref>PMID:32573439</ref> <ref>PMID:34115842</ref> <ref>PMID:35247700</ref> <ref>PMID:36170828</ref> <ref>PMID:36745679</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with defective protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). How Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies.
-Authors:
+,  PMID:36170828<ref>PMID:36170828</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7tts" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Bos taurus]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Cupo RR]]
+[[Category: Rizo AN]]

7tts

From Proteopedia

Current revision

Skd3, hexamer, filtered

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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