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6eun

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Crystal structure of Neisseria meningitidis vaccine antigen NadA variant 3

Structural highlights

6eun is a 3 chain structure with sequence from Neisseria meningitidis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.45Å
Ligands:	, , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NADA3_NEIMI Adheres to and induces bacterial uptake by human epithelial cells in a microfilament-dependent process. Binding is reduced by pronase treatment, suggesting there is a protein receptor on the human cells (PubMed:15660996, PubMed:30327444). Possible human protein receptors include integrin beta-1 (ITGB1) and oxidized low-density lipoprotein receptor 1 (OLR1) (Probable). Binds to extracellular human Hsp90 (preferentially the beta isoform, HSP90AB1) on monocytes, binding stimulates monocytes in a TLR4-dependent fashion, polymixin B, which binds NadA, blocks the activation. Hsp90 is probably not the first receptor on human monocytes (PubMed:21949862). Non-membrane anchored protein (residues 24-350) is internalized into human epithelial cells by hijacking the endosome recycling pathway and may be recycled back to the cell surface, which might aid transcellular trafficking of the bacteria (PubMed:25347845). A bacterial cell surface protein; antisera against this protein induce complement-mediated killing of this and other strains (PubMed:12045242).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Neisseria meningitidis serogroup B (MenB) is a major cause of sepsis and invasive meningococcal disease. A multicomponent vaccine, 4CMenB, is approved for protection against MenB. Neisserial adhesin A (NadA) is one of the main vaccine antigens, acts in host cell adhesion, and may influence colonization and invasion. Six major genetic variants of NadA exist and can be classified into immunologically distinct groups I and II. Knowledge of the crystal structure of the 4CMenB vaccine component NadA3 (group I) would improve understanding of its immunogenicity, folding, and functional properties and might aid antigen design. Here, X-ray crystallography, biochemical, and cellular studies were used to deeply characterize NadA3. The NadA3 crystal structure is reported; it revealed two unexpected regions of undecad coiled-coil motifs and other conformational differences from NadA5 (group II) not predicted by previous analyses. Structure-guided engineering was performed to increase NadA3 thermostability, and a second crystal structure confirmed the improved packing. Functional NadA3 residues mediating interactions with human receptor LOX-1 were identified. Also, for two protective vaccine-elicited human monoclonal antibodies (5D11, 12H11), we mapped key NadA3 epitopes. These vaccine-elicited human MAbs competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. The data presented provide a significant advance in the understanding of the structure, immunogenicity and function of NadA, one of the main antigens of the multicomponent meningococcus B vaccine.IMPORTANCE The bacterial microbe Neisseria meningitidis serogroup B (MenB) is a major cause of devastating meningococcal disease. An approved multicomponent vaccine, 4CMenB, protects against MenB. Neisserial adhesin A (NadA) is a key vaccine antigen and acts in host cell-pathogen interactions. We investigated the 4CMenB vaccine component NadA3 in order to improve the understanding of its immunogenicity, structure, and function and to aid antigen design. We report crystal structures of NadA3, revealing unexpected structural motifs, and other conformational differences from the NadA5 orthologue studied previously. We performed structure-based antigen design to engineer increased NadA3 thermostability. Functional NadA3 residues mediating interactions with the human receptor LOX-1 and vaccine-elicited human antibodies were identified. These antibodies competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. Our data provide a significant advance in the overall understanding of the 4CMenB vaccine antigen NadA.

NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies.,Liguori A, Dello Iacono L, Maruggi G, Benucci B, Merola M, Lo Surdo P, Lopez-Sagaseta J, Pizza M, Malito E, Bottomley MJ MBio. 2018 Oct 16;9(5). pii: mBio.01914-18. doi: 10.1128/mBio.01914-18. PMID:30327444^[7]

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

References

↑ Comanducci M, Bambini S, Brunelli B, Adu-Bobie J, Aricò B, Capecchi B, Giuliani MM, Masignani V, Santini L, Savino S, Granoff DM, Caugant DA, Pizza M, Rappuoli R, Mora M. NadA, a novel vaccine candidate of Neisseria meningitidis. J Exp Med. 2002 Jun 3;195(11):1445-54. PMID:12045242 doi:10.1084/jem.20020407
↑ Capecchi B, Adu-Bobie J, Di Marcello F, Ciucchi L, Masignani V, Taddei A, Rappuoli R, Pizza M, Aricò B. Neisseria meningitidis NadA is a new invasin which promotes bacterial adhesion to and penetration into human epithelial cells. Mol Microbiol. 2005 Feb;55(3):687-98. PMID:15660996 doi:10.1111/j.1365-2958.2004.04423.x
↑ Cecchini P, Tavano R, Polverino de Laureto P, Franzoso S, Mazzon C, Montanari P, Papini E. The soluble recombinant Neisseria meningitidis adhesin NadA(Δ351-405) stimulates human monocytes by binding to extracellular Hsp90. PLoS One. 2011;6(9):e25089. PMID:21949862 doi:10.1371/journal.pone.0025089
↑ Bozza G, Capitani M, Montanari P, Benucci B, Biancucci M, Nardi-Dei V, Caproni E, Barrile R, Picciani B, Savino S, Aricò B, Rappuoli R, Pizza M, Luini A, Sallese M, Merola M. Role of ARF6, Rab11 and external Hsp90 in the trafficking and recycling of recombinant-soluble Neisseria meningitidis adhesin A (rNadA) in human epithelial cells. PLoS One. 2014 Oct 27;9(10):e110047. PMID:25347845 doi:10.1371/journal.pone.0110047
↑ Liguori A, Dello Iacono L, Maruggi G, Benucci B, Merola M, Lo Surdo P, Lopez-Sagaseta J, Pizza M, Malito E, Bottomley MJ. NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies. MBio. 2018 Oct 16;9(5). pii: mBio.01914-18. doi: 10.1128/mBio.01914-18. PMID:30327444 doi:http://dx.doi.org/10.1128/mBio.01914-18
↑ Scietti L, Sampieri K, Pinzuti I, Bartolini E, Benucci B, Liguori A, Haag AF, Lo Surdo P, Pansegrau W, Nardi-Dei V, Santini L, Arora S, Leber X, Rindi S, Savino S, Costantino P, Maione D, Merola M, Speziale P, Bottomley MJ, Bagnoli F, Masignani V, Pizza M, Scharenberg M, Schlaeppi JM, Nissum M, Liberatori S. Exploring host-pathogen interactions through genome wide protein microarray analysis. Sci Rep. 2016 Jun 15;6:27996. PMID:27302108 doi:10.1038/srep27996
↑ Liguori A, Dello Iacono L, Maruggi G, Benucci B, Merola M, Lo Surdo P, Lopez-Sagaseta J, Pizza M, Malito E, Bottomley MJ. NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies. MBio. 2018 Oct 16;9(5). pii: mBio.01914-18. doi: 10.1128/mBio.01914-18. PMID:30327444 doi:http://dx.doi.org/10.1128/mBio.01914-18

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Crystal structure of Neisseria meningitidis vaccine antigen NadA variant 3==
-<StructureSection load='6eun' size='340' side='right' caption='[[6eun]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
+<StructureSection load='6eun' size='340' side='right'caption='[[6eun]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6eun]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/"diplokokkus_intracellularis_meningitidis"_(sic)_weichselbaum_1887 "diplokokkus intracellularis meningitidis" (sic) weichselbaum 1887]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6eun]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Neisseria_meningitidis Neisseria meningitidis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EUN FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=P4G:1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE'>P4G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.45&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">nadA, A6L27_04700 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=487 "Diplokokkus intracellularis meningitidis" (sic) Weichselbaum 1887])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=P4G:1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE'>P4G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6eun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eun OCA], [http://pdbe.org/6eun PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eun RCSB], [http://www.ebi.ac.uk/pdbsum/6eun PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eun ProSAT]</span></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=6eun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eun OCA], [https://pdbe.org/6eun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eun RCSB], [https://www.ebi.ac.uk/pdbsum/6eun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eun ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/NADA3_NEIMI NADA3_NEIMI] Adheres to and induces bacterial uptake by human epithelial cells in a microfilament-dependent process. Binding is reduced by pronase treatment, suggesting there is a protein receptor on the human cells (PubMed:15660996, PubMed:30327444). Possible human protein receptors include integrin beta-1 (ITGB1) and oxidized low-density lipoprotein receptor 1 (OLR1) (Probable). Binds to extracellular human Hsp90 (preferentially the beta isoform, HSP90AB1) on monocytes, binding stimulates monocytes in a TLR4-dependent fashion, polymixin B, which binds NadA, blocks the activation. Hsp90 is probably not the first receptor on human monocytes (PubMed:21949862). Non-membrane anchored protein (residues 24-350) is internalized into human epithelial cells by hijacking the endosome recycling pathway and may be recycled back to the cell surface, which might aid transcellular trafficking of the bacteria (PubMed:25347845). A bacterial cell surface protein; antisera against this protein induce complement-mediated killing of this and other strains (PubMed:12045242).<ref>PMID:12045242</ref> <ref>PMID:15660996</ref> <ref>PMID:21949862</ref> <ref>PMID:25347845</ref> <ref>PMID:30327444</ref> <ref>PMID:27302108</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 19: @@
 </div>
 <div class="pdbe-citations 6eun" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Adhesin 3D structures|Adhesin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Bottomley, M J]]
+[[Category: Large Structures]]
-[[Category: Iacono, L Dello]]
+[[Category: Neisseria meningitidis]]
-[[Category: Liguori, A]]
+[[Category: Bottomley MJ]]
-[[Category: Malito, E]]
+[[Category: Dello Iacono L]]
-[[Category: Antigen]]
+[[Category: Liguori A]]
-[[Category: Cell adhesion]]
+[[Category: Malito E]]
-[[Category: Trimeric autotransporter adhesin]]

6eun

From Proteopedia

Current revision

Crystal structure of Neisseria meningitidis vaccine antigen NadA variant 3

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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