6ze9

From Proteopedia

(Difference between revisions)

Revision as of 10:09, 12 August 2020

Non-native fold of the putative VPS39 zinc finger domain

Structural highlights

6ze9 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	VPS39, KIAA0770, TLP, VAM6 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[VPS39_HUMAN] Regulator of TGF-beta/activin signaling, inhibiting SMAD3- and activating SMAD2-dependent transcription. Acts by interfering with SMAD3/SMAD4 complex formation, this would lead to inhibition of SMAD3-dependent transcription and relieve SMAD3 inhibition of SMAD2-dependent promoters, thus increasing SMAD2-dependent transcription. Does not affect TGF-beta-induced SMAD2 or SMAD3 phosphorylation, nor SMAD2/SMAD4 complex formation.^[1] Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act in part as a component of the putative HOPS endosomal tethering complex which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes (PubMed:23351085). Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes (PubMed:11448994, PubMed:23351085, PubMed:23167963). Required for fusion of endosomes and autophagosomes with lysosomes (PubMed:25783203).^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Background: The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is involved in regulating the fusion of late endosomes and autophagosomes with lysosomes in eukaryotes. The C-terminal regions of several HOPS components have been shown to be required for correct complex assembly, including the C-terminal really interesting new gene (RING) zinc finger domains of HOPS components VPS18 and VPS41. We sought to structurally characterise the putative C-terminal zinc finger domain of VPS39, which we hypothesised may be important for binding of VPS39 to cellular partners or to other HOPS components. Methods: We recombinantly expressed, purified and solved the crystal structure of the proposed zinc-binding region of VPS39. Results: In the structure, this region forms an anti-parallel beta-hairpin that is incorporated into a homotetrameric eight-stranded beta-barrel. However, the fold is stabilised by coordination of zinc ions by residues from the purification tag and an intramolecular disulphide bond between two predicted zinc ligands. Conclusions: We solved the structure of the VPS39 C-terminal domain adopting a non-native fold. Our work highlights the risk of non-native folds when purifying small zinc-containing domains with hexahistidine tags. However, the non-native structure we observe may have implications for rational protein design.

Non-native fold of the putative VPS39 zinc finger domain.,Butt BG, Scourfield EJ, Graham SC Wellcome Open Res. 2020 Jul 1;5:154. doi: 10.12688/wellcomeopenres.16078.1., eCollection 2020. PMID:32724865^[6]

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

References

↑ Felici A, Wurthner JU, Parks WT, Giam LR, Reiss M, Karpova TS, McNally JG, Roberts AB. TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling. EMBO J. 2003 Sep 1;22(17):4465-77. doi: 10.1093/emboj/cdg428. PMID:12941698 doi:http://dx.doi.org/10.1093/emboj/cdg428
↑ Caplan S, Hartnell LM, Aguilar RC, Naslavsky N, Bonifacino JS. Human Vam6p promotes lysosome clustering and fusion in vivo. J Cell Biol. 2001 Jul 9;154(1):109-22. doi: 10.1083/jcb.200102142. PMID:11448994 doi:http://dx.doi.org/10.1083/jcb.200102142
↑ Pols MS, ten Brink C, Gosavi P, Oorschot V, Klumperman J. The HOPS proteins hVps41 and hVps39 are required for homotypic and heterotypic late endosome fusion. Traffic. 2013 Feb;14(2):219-32. doi: 10.1111/tra.12027. Epub 2012 Dec 12. PMID:23167963 doi:http://dx.doi.org/10.1111/tra.12027
↑ Wartosch L, Gunesdogan U, Graham SC, Luzio JP. Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes. Traffic. 2015 Jul;16(7):727-42. doi: 10.1111/tra.12283. Epub 2015 Apr 30. PMID:25783203 doi:http://dx.doi.org/10.1111/tra.12283
↑ Solinger JA, Spang A. Tethering complexes in the endocytic pathway: CORVET and HOPS. FEBS J. 2013 Jun;280(12):2743-57. doi: 10.1111/febs.12151. Epub 2013 Feb 21. PMID:23351085 doi:http://dx.doi.org/10.1111/febs.12151
↑ Butt BG, Scourfield EJ, Graham SC. Non-native fold of the putative VPS39 zinc finger domain. Wellcome Open Res. 2020 Jul 1;5:154. doi: 10.12688/wellcomeopenres.16078.1., eCollection 2020. PMID:32724865 doi:http://dx.doi.org/10.12688/wellcomeopenres.16078.1

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6ze9"

@@ Line 1: / Line 1: @@
 ==Non-native fold of the putative VPS39 zinc finger domain==
-<StructureSection load='6ze9' size='340' side='right'caption='[[6ze9]]' scene=''>
+<StructureSection load='6ze9' size='340' side='right'caption='[[6ze9]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZE9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZE9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ze9]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZE9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZE9 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ze9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ze9 OCA], [http://pdbe.org/6ze9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ze9 RCSB], [http://www.ebi.ac.uk/pdbsum/6ze9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ze9 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VPS39, KIAA0770, TLP, VAM6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ze9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ze9 OCA], [http://pdbe.org/6ze9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ze9 RCSB], [http://www.ebi.ac.uk/pdbsum/6ze9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ze9 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/VPS39_HUMAN VPS39_HUMAN]] Regulator of TGF-beta/activin signaling, inhibiting SMAD3- and activating SMAD2-dependent transcription. Acts by interfering with SMAD3/SMAD4 complex formation, this would lead to inhibition of SMAD3-dependent transcription and relieve SMAD3 inhibition of SMAD2-dependent promoters, thus increasing SMAD2-dependent transcription. Does not affect TGF-beta-induced SMAD2 or SMAD3 phosphorylation, nor SMAD2/SMAD4 complex formation.<ref>PMID:12941698</ref>   Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act in part as a component of the putative HOPS endosomal tethering complex which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed to be recruited to Rab7 on the late endosomal membrane and to regulate late endocytic, phagocytic and autophagic traffic towards lysosomes (PubMed:23351085). Involved in homotypic vesicle fusions between late endosomes and in heterotypic fusions between late endosomes and lysosomes (PubMed:11448994, PubMed:23351085, PubMed:23167963). Required for fusion of endosomes and autophagosomes with lysosomes (PubMed:25783203).<ref>PMID:11448994</ref> <ref>PMID:23167963</ref> <ref>PMID:25783203</ref> <ref>PMID:23351085</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Background: The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is involved in regulating the fusion of late endosomes and autophagosomes with lysosomes in eukaryotes. The C-terminal regions of several HOPS components have been shown to be required for correct complex assembly, including the C-terminal really interesting new gene (RING) zinc finger domains of HOPS components VPS18 and VPS41. We sought to structurally characterise the putative C-terminal zinc finger domain of VPS39, which we hypothesised may be important for binding of VPS39 to cellular partners or to other HOPS components. Methods: We recombinantly expressed, purified and solved the crystal structure of the proposed zinc-binding region of VPS39. Results: In the structure, this region forms an anti-parallel beta-hairpin that is incorporated into a homotetrameric eight-stranded beta-barrel. However, the fold is stabilised by coordination of zinc ions by residues from the purification tag and an intramolecular disulphide bond between two predicted zinc ligands. Conclusions: We solved the structure of the VPS39 C-terminal domain adopting a non-native fold. Our work highlights the risk of non-native folds when purifying small zinc-containing domains with hexahistidine tags. However, the non-native structure we observe may have implications for rational protein design.
+Non-native fold of the putative VPS39 zinc finger domain.,Butt BG, Scourfield EJ, Graham SC Wellcome Open Res. 2020 Jul 1;5:154. doi: 10.12688/wellcomeopenres.16078.1., eCollection 2020. PMID:32724865<ref>PMID:32724865</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6ze9" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Butt BG]]
+[[Category: Butt, B G]]
-[[Category: Graham SC]]
+[[Category: Graham, S C]]
+[[Category: Endocytosis]]
+[[Category: Hop]]
+[[Category: Membrane trafficking]]

6ze9

From Proteopedia

Revision as of 10:09, 12 August 2020

Non-native fold of the putative VPS39 zinc finger domain

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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