8q1k

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Current revision (08:03, 6 December 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 8q1k is ON HOLD until Paper Publication
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==Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation==
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<StructureSection load='8q1k' size='340' side='right'caption='[[8q1k]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[8q1k]] 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=8Q1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8Q1K FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.51&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OCS:CYSTEINESULFONIC+ACID'>OCS</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8q1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8q1k OCA], [https://pdbe.org/8q1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8q1k RCSB], [https://www.ebi.ac.uk/pdbsum/8q1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8q1k ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PLD3_HUMAN PLD3_HUMAN] Spinocerebellar ataxia type 46. The disease may be caused by variants affecting the gene represented in this entry. There is limited evidences for implication of PLD3 in SCA46. Knockout mice do not present signs of cerebellar degeneration or spinocerebellar ataxia at 9 months of age, challenging the interpretation of the suggested loss-of-function mechanism for PLD3 as the SCA46-causative gene.<ref>PMID:30312375</ref> Genetic variants in PLD3 have been suggested to be associated with an increased risk for Alzheimer disease (PubMed:24336208, PubMed:25832409). Further studies, however, did not support PLD3 involvement in this disease (PubMed:25832408, PubMed:25832411, PubMed:25832413, PubMed:25832410, PubMed:26411346). Futhermore, it is controversial whether PLD3 plays a role in amyloid precursor protein processing (APP) or not (PubMed:24336208). In a relevant Alzheimer's disease mouse model PLD3 deficiency does not affect APP metabolism or amyloid plaque burden (PubMed:28128235). However one study shown that PLD3 influences APP processing (PubMed:24336208).<ref>PMID:24336208</ref> <ref>PMID:25832408</ref> <ref>PMID:25832409</ref> <ref>PMID:25832410</ref> <ref>PMID:25832411</ref> <ref>PMID:25832413</ref> <ref>PMID:26411346</ref> <ref>PMID:28128235</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/PLD3_HUMAN PLD3_HUMAN] 5'->3' DNA exonuclease which digests single-stranded DNA (ssDNA) (PubMed:30312375). Regulates inflammatory cytokine responses via the degradation of nucleic acids, by reducing the concentration of ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in collaboration with PLD4 (By similarity). May be important in myotube formation (PubMed:22428023). Plays a role in lysosomal homeostasis (PubMed:28128235). Involved in the regulation of endosomal protein sorting (PubMed:29368044).[UniProtKB:O35405]<ref>PMID:22428023</ref> <ref>PMID:28128235</ref> <ref>PMID:29368044</ref> <ref>PMID:30312375</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The phospholipase D (PLD) family is comprised of enzymes bearing phospholipase activity towards lipids or endo- and exonuclease activity towards nucleic acids. PLD3 is synthesized as a type II transmembrane protein and proteolytically cleaved in lysosomes, yielding a soluble active form. The deficiency of PLD3 leads to the slowed degradation of nucleic acids in lysosomes and chronic activation of nucleic acid-specific intracellular toll-like receptors. While the mechanism of PLD phospholipase activity has been extensively characterized, not much is known about how PLDs bind and hydrolyze nucleic acids. Here, we determined the high-resolution crystal structure of the luminal N-glycosylated domain of human PLD3 in its apo- and single-stranded DNA-bound forms. PLD3 has a typical phospholipase fold and forms homodimers with two independent catalytic centers via a newly identified dimerization interface. The structure of PLD3 in complex with an ssDNA-derived thymidine product in the catalytic center provides insights into the substrate binding mode of nucleic acids in the PLD family. Our structural data suggest a mechanism for substrate binding and nuclease activity in the PLD family and provide the structural basis to design immunomodulatory drugs targeting PLD3.
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Authors: Roske, Y., Daumke, O., Damme, M.
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Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation.,Roske Y, Cappel C, Cremer N, Hoffmann P, Koudelka T, Tholey A, Heinemann U, Daumke O, Damme M Nucleic Acids Res. 2023 Nov 22:gkad1114. doi: 10.1093/nar/gkad1114. PMID:37994783<ref>PMID:37994783</ref>
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Description: Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5'' exonuclease-mediated nucleic acid degradation
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Damme, M]]
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<div class="pdbe-citations 8q1k" style="background-color:#fffaf0;"></div>
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[[Category: Roske, Y]]
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== References ==
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[[Category: Daumke, O]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Damme M]]
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[[Category: Daumke O]]
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[[Category: Roske Y]]

Current revision

Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation

PDB ID 8q1k

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