NADA3_NEIMI
ID NADA3_NEIMI Reviewed; 405 AA.
AC P0DV44;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 25-MAY-2022, sequence version 1.
DT 03-AUG-2022, entry version 2.
DE RecName: Full=Neisseria adhesin A {ECO:0000303|PubMed:12045242};
DE Short=NadA variant 3 {ECO:0000303|PubMed:15660996};
DE Flags: Precursor;
GN Name=nadA {ECO:0000303|PubMed:12045242}; Synonyms=nadA3 {ECO:0000305};
OS Neisseria meningitidis serogroup B.
OC Bacteria; Proteobacteria; Betaproteobacteria; Neisseriales; Neisseriaceae;
OC Neisseria.
OX NCBI_TaxID=491;
RN [1] {ECO:0000312|EMBL:AAM53086.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SUBUNIT, SUBCELLULAR LOCATION,
RP INDUCTION, AND BIOTECHNOLOGY.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b
RC {ECO:0000312|EMBL:AAM53086.1};
RX PubMed=12045242; DOI=10.1084/jem.20020407;
RA Comanducci M., Bambini S., Brunelli B., Adu-Bobie J., Arico B.,
RA Capecchi B., Giuliani M.M., Masignani V., Santini L., Savino S.,
RA Granoff D.M., Caugant D.A., Pizza M., Rappuoli R., Mora M.;
RT "NadA, a novel vaccine candidate of Neisseria meningitidis.";
RL J. Exp. Med. 195:1445-1454(2002).
RN [2]
RP FUNCTION IN BACTERIAL ADHESION AND UPTAKE, SUBUNIT, SUBCELLULAR LOCATION,
RP DOMAIN, AND MUTAGENESIS OF 1-MET--ALA-23; 24-ALA--TYR-42; 43-ASN--ASP-70;
RP 71-ALA--GLY-83 AND 351-ARG--TRP-405.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b;
RX PubMed=15660996; DOI=10.1111/j.1365-2958.2004.04423.x;
RA Capecchi B., Adu-Bobie J., Di Marcello F., Ciucchi L., Masignani V.,
RA Taddei A., Rappuoli R., Pizza M., Arico B.;
RT "Neisseria meningitidis NadA is a new invasin which promotes bacterial
RT adhesion to and penetration into human epithelial cells.";
RL Mol. Microbiol. 55:687-698(2005).
RN [3]
RP BIOTECHNOLOGY.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b;
RX PubMed=16825336; DOI=10.1073/pnas.0603940103;
RA Giuliani M.M., Adu-Bobie J., Comanducci M., Arico B., Savino S.,
RA Santini L., Brunelli B., Bambini S., Biolchi A., Capecchi B., Cartocci E.,
RA Ciucchi L., Di Marcello F., Ferlicca F., Galli B., Luzzi E., Masignani V.,
RA Serruto D., Veggi D., Contorni M., Morandi M., Bartalesi A., Cinotti V.,
RA Mannucci D., Titta F., Ovidi E., Welsch J.A., Granoff D., Rappuoli R.,
RA Pizza M.;
RT "A universal vaccine for serogroup B meningococcus.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:10834-10839(2006).
RN [4]
RP SUBUNIT.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b;
RX PubMed=19356620; DOI=10.1016/j.vaccine.2009.01.099;
RA Magagnoli C., Bardotti A., De Conciliis G., Galasso R., Tomei M., Campa C.,
RA Pennatini C., Cerchioni M., Fabbri B., Giannini S., Mattioli G.L.,
RA Biolchi A., D'Ascenzi S., Helling F.;
RT "Structural organization of NadADelta(351-405), a recombinant MenB vaccine
RT component, by its physico-chemical characterization at drug substance
RT level.";
RL Vaccine 27:2156-2170(2009).
RN [5]
RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF 30-VAL--LYS-87;
RP 88-LYS--ILE-150; 180-GLU--ASP-218; 219-ALA--ILE-288 AND 270-ALA--ARG-315.
RX PubMed=20971901; DOI=10.1128/jb.00430-10;
RA Tavano R., Capecchi B., Montanari P., Franzoso S., Marin O., Sztukowska M.,
RA Cecchini P., Segat D., Scarselli M., Arico B., Papini E.;
RT "Mapping of the Neisseria meningitidis NadA cell-binding site: relevance of
RT predicted {alpha}-helices in the NH2-terminal and dimeric coiled-coil
RT regions.";
RL J. Bacteriol. 193:107-115(2011).
RN [6]
RP FUNCTION, AND INTERACTION WITH HUMAN HSP90-BETA.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b;
RX PubMed=21949862; DOI=10.1371/journal.pone.0025089;
RA Cecchini P., Tavano R., Polverino de Laureto P., Franzoso S., Mazzon C.,
RA Montanari P., Papini E.;
RT "The soluble recombinant Neisseria meningitidis adhesin NadA(Delta351-405)
RT stimulates human monocytes by binding to extracellular Hsp90.";
RL PLoS ONE 6:e25089-e25089(2011).
RN [7]
RP FUNCTION, AND INTERACTION WITH HUMAN HSP90.
RX PubMed=22066472; DOI=10.1111/j.1462-5822.2011.01722.x;
RA Montanari P., Bozza G., Capecchi B., Caproni E., Barrile R., Norais N.,
RA Capitani M., Sallese M., Cecchini P., Ciucchi L., Gao Z., Rappuoli R.,
RA Pizza M., Arico B., Merola M.;
RT "Human heat shock protein (Hsp) 90 interferes with Neisseria meningitidis
RT adhesin A (NadA)-mediated adhesion and invasion.";
RL Cell. Microbiol. 14:368-385(2012).
RN [8]
RP POSSIBLE FUNCTION IN UPTAKE BY HUMAN CELLS.
RX PubMed=25347845; DOI=10.1371/journal.pone.0110047;
RA Bozza G., Capitani M., Montanari P., Benucci B., Biancucci M.,
RA Nardi-Dei V., Caproni E., Barrile R., Picciani B., Savino S., Arico B.,
RA Rappuoli R., Pizza M., Luini A., Sallese M., Merola M.;
RT "Role of ARF6, Rab11 and external Hsp90 in the trafficking and recycling of
RT recombinant-soluble Neisseria meningitidis adhesin A (rNadA) in human
RT epithelial cells.";
RL PLoS ONE 9:e110047-e110047(2014).
RN [9]
RP ELECTRON MICROSCOPY OF 24-350, AND DOMAIN.
RC STRAIN=M01-240320;
RX PubMed=25404323; DOI=10.1073/pnas.1419686111;
RA Malito E., Biancucci M., Faleri A., Ferlenghi I., Scarselli M., Maruggi G.,
RA Lo Surdo P., Veggi D., Liguori A., Santini L., Bertoldi I., Petracca R.,
RA Marchi S., Romagnoli G., Cartocci E., Vercellino I., Savino S.,
RA Spraggon G., Norais N., Pizza M., Rappuoli R., Masignani V.,
RA Bottomley M.J.;
RT "Structure of the meningococcal vaccine antigen NadA and epitope mapping of
RT a bactericidal antibody.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:17128-17133(2014).
RN [10]
RP FUNCTION, SUBUNIT, INTERACTION WITH HUMAN LOX-1 (OLR1), AND DOMAIN.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b;
RX PubMed=27302108; DOI=10.1038/srep27996;
RA Scietti L., Sampieri K., Pinzuti I., Bartolini E., Benucci B., Liguori A.,
RA Haag A.F., Lo Surdo P., Pansegrau W., Nardi-Dei V., Santini L., Arora S.,
RA Leber X., Rindi S., Savino S., Costantino P., Maione D., Merola M.,
RA Speziale P., Bottomley M.J., Bagnoli F., Masignani V., Pizza M.,
RA Scharenberg M., Schlaeppi J.M., Nissum M., Liberatori S.;
RT "Exploring host-pathogen interactions through genome wide protein
RT microarray analysis.";
RL Sci. Rep. 6:27996-27996(2016).
RN [11] {ECO:0007744|PDB:6EUN, ECO:0007744|PDB:6EUP}
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 24-170, SUBUNIT, INTERACTION WITH
RP HUMAN LOX-1 (OLR1), DOMAIN, AND MUTAGENESIS OF 33-ALA--ALA-39;
RP 33-ALA--ILE-38; ALA-33 AND TYR-42.
RC STRAIN=CCUG 23106 / 2996 / Serogroup B / Serotype 2b;
RX PubMed=30327444; DOI=10.1128/mbio.01914-18;
RA Liguori A., Dello Iacono L., Maruggi G., Benucci B., Merola M.,
RA Lo Surdo P., Lopez-Sagaseta J., Pizza M., Malito E., Bottomley M.J.;
RT "NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions
RT Competed by Meningococcus B Vaccine-Elicited Human Antibodies.";
RL MBio 9:0-0(2018).
CC -!- FUNCTION: Adheres to and induces bacterial uptake by human epithelial
CC cells in a microfilament-dependent process. Binding is reduced by
CC pronase treatment, suggesting there is a protein receptor on the human
CC cells (PubMed:15660996, PubMed:30327444). Possible human protein
CC receptors include integrin beta-1 (ITGB1) and oxidized low-density
CC lipoprotein receptor 1 (OLR1) (Probable). Binds to extracellular human
CC Hsp90 (preferentially the beta isoform, HSP90AB1) on monocytes, binding
CC stimulates monocytes in a TLR4-dependent fashion, polymixin B, which
CC binds NadA, blocks the activation. Hsp90 is probably not the first
CC receptor on human monocytes (PubMed:21949862). Non-membrane anchored
CC protein (residues 24-350) is internalized into human epithelial cells
CC by hijacking the endosome recycling pathway and may be recycled back to
CC the cell surface, which might aid transcellular trafficking of the
CC bacteria (PubMed:25347845). A bacterial cell surface protein; antisera
CC against this protein induce complement-mediated killing of this and
CC other strains (PubMed:12045242). {ECO:0000269|PubMed:12045242,
CC ECO:0000269|PubMed:15660996, ECO:0000269|PubMed:21949862,
CC ECO:0000269|PubMed:25347845, ECO:0000269|PubMed:30327444,
CC ECO:0000305|PubMed:27302108}.
CC -!- SUBUNIT: The non-membrane anchored protein (residues 24-350) probably
CC forms a homotrimer; it is assumed the mature protein forms trimers in
CC situ (Probable). The mature protein without the membrane-targeting
CC segment (residues 24-350) binds to human heat shock 90 beta protein
CC (HSP90AB1) both in vitro and when incubated with human monocytes
CC (PubMed:21949862). A subsequent paper showed binding of the same
CC fragment in epithelial cells to both HSP90AA1 and HSP90AB1; in vitro
CC the interaction is stabilized by ADP and the Hsp90 inhibitor 17-AAG
CC (17-N-allylamino-17-demethoxygeldanamycin), in vitro and in vivo both
CC interactions are inhibited by ATP (PubMed:21949862, PubMed:22066472).
CC Binds human oxidized low-density lipoprotein receptor 1 (LOX-1, OLR1)
CC in protein microarrays, in solution and when LOX-1 is expressed on the
CC cell surface. Binds via the head and the beginning of the coiled stalk
CC (residues 24-170); binding can be abrogated by monoclonal antibodies
CC against those specific regions of NadA. Other potential binding
CC partners were identified but not characterized in the same study
CC (PubMed:27302108). Forms high molecular weight oligomers in whole cell
CC extracts that are not disrupted by boiling in SDS buffer
CC (PubMed:12045242, PubMed:15660996). {ECO:0000269|PubMed:12045242,
CC ECO:0000269|PubMed:15660996, ECO:0000269|PubMed:21949862,
CC ECO:0000269|PubMed:22066472, ECO:0000269|PubMed:27302108,
CC ECO:0000305|PubMed:19356620, ECO:0000305|PubMed:27302108,
CC ECO:0000305|PubMed:30327444}.
CC -!- SUBCELLULAR LOCATION: Cell outer membrane
CC {ECO:0000269|PubMed:15660996}. Cell surface
CC {ECO:0000269|PubMed:12045242, ECO:0000269|PubMed:15660996,
CC ECO:0000269|PubMed:20971901}.
CC -!- INDUCTION: Barely visible in early log phase, levels increase to a
CC maximum in stationary phase cells (at protein level).
CC {ECO:0000269|PubMed:12045242}.
CC -!- DOMAIN: The signal peptide, cleaved at the inner membrane, guides the
CC autotransporter protein to the periplasmic space. Insertion of the C-
CC terminal translocator domain in the outer membrane forms a hydrophilic
CC pore for the translocation of the passenger domain to the bacterial
CC cell surface (By similarity). The N-terminal head domain (24-87) as
CC well as the dimeric coiled-coil region (88-132) are required for
CC binding to human cells. The C-terminal translocator domain (maximally
CC 54 residues) probably targets the protein to the outer membrane. The
CC middle coiled section is responsible for oligomerization (Probable)
CC (PubMed:20971901). In transmission electron microscopy the non-membrane
CC bound mature protein (residues 24-350) has a thin elongated structure
CC about 300 Angstroms long that is broader at one end (probably the
CC head). Both linear and curved NadA3 molecules were observed. The head
CC domain is recognized by monoclonal antibodies (PubMed:25404323). A
CC structure encompassing residues 24-170 forms a 160 Angstroms-long
CC coiled-coil stalk. The wing-like structures in this variant (residues
CC 54-72) interrupt the coiled-coil stalk; the pack differently against
CC the stalk than in variant 5 (PubMed:30327444). The 24-170 residue
CC fragment binds human LOX-1 (OLR1) (PubMed:27302108).
CC {ECO:0000250|UniProtKB:P0C2W0, ECO:0000269|PubMed:20971901,
CC ECO:0000269|PubMed:25404323, ECO:0000269|PubMed:27302108,
CC ECO:0000269|PubMed:30327444, ECO:0000305|PubMed:15660996}.
CC -!- BIOTECHNOLOGY: Several alleles exist that vary in length, this is
CC allele 3; alleles 1, 2 and 3 generate cross-bactericidal antibodies.
CC About 50% of hypervirulent serogroup B N.meningitidis encode this
CC protein (PubMed:12045242). This is the variant used in the 4CMenB
CC (Bexsero) vaccine (PubMed:25404323). This is the variant used in the
CC 5CVMB vaccine (PubMed:16825336). {ECO:0000269|PubMed:12045242,
CC ECO:0000269|PubMed:16825336, ECO:0000269|PubMed:25404323}.
CC -!- SIMILARITY: Belongs to the autotransporter-2 (AT-2) (TC 1.B.40) family.
CC {ECO:0000305}.
CC -!- CAUTION: The gene name nadA has also been given to quinolinate
CC synthase.
CC -!- WEB RESOURCE: Name=Bexsero meningococcal group B Vaccine;
CC URL="https://www.ema.europa.eu/en/medicines/human/EPAR/bexsero";
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DR EMBL; AF452470; AAM53086.1; -; Genomic_DNA.
DR PDB; 6EUN; X-ray; 2.45 A; A/B/C=24-170.
DR PDB; 6EUP; X-ray; 2.65 A; A/B/C=24-170.
DR PDBsum; 6EUN; -.
DR PDBsum; 6EUP; -.
DR GO; GO:0009279; C:cell outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR InterPro; IPR045584; Pilin-like.
DR InterPro; IPR005594; YadA_C.
DR Pfam; PF03895; YadA_anchor; 1.
DR SUPFAM; SSF54523; SSF54523; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell adhesion; Cell outer membrane; Coiled coil; Membrane;
KW Signal; Transmembrane; Transmembrane beta strand; Virulence.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT CHAIN 24..405
FT /note="Neisseria adhesin A"
FT /evidence="ECO:0000255"
FT /id="PRO_0000455272"
FT TRANSMEM 350..360
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:A1JUB7"
FT TRANSMEM 364..375
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:A1JUB7"
FT TRANSMEM 382..388
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:A1JUB7"
FT TRANSMEM 394..405
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:A1JUB7"
FT REGION 24..87
FT /note="Head domain"
FT /evidence="ECO:0000305|PubMed:15660996,
FT ECO:0000305|PubMed:30327444"
FT REGION 88..350
FT /note="Coiled stalk domain"
FT /evidence="ECO:0000305|PubMed:15660996,
FT ECO:0000305|PubMed:30327444"
FT REGION 312..350
FT /note="Outer membrane translocation of the passenger
FT domain"
FT /evidence="ECO:0000250|UniProtKB:P0C2W0"
FT REGION 351..405
FT /note="Translocator domain"
FT /evidence="ECO:0000250|UniProtKB:P0C2W0,
FT ECO:0000305|PubMed:15660996, ECO:0000305|PubMed:30327444"
FT COILED 87..170
FT /evidence="ECO:0000305|PubMed:12045242,
FT ECO:0007744|PDB:6EUN, ECO:0007744|PDB:6EUP"
FT COILED 181..329
FT /evidence="ECO:0000305|PubMed:12045242"
FT MUTAGEN 1..23
FT /note="Missing: No longer surface-exposed."
FT /evidence="ECO:0000269|PubMed:15660996"
FT MUTAGEN 24..42
FT /note="Missing: No longer adheres to human epithelial
FT cells, oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:15660996"
FT MUTAGEN 30..87
FT /note="Missing: No longer adheres to human epithelial
FT cells, oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:20971901"
FT MUTAGEN 33..39
FT /note="AATVAIA->IATVAIV: Increased thermostability."
FT /evidence="ECO:0000269|PubMed:30327444"
FT MUTAGEN 33..38
FT /note="AATVAI->IATVAL: Increased thermostability. Loss of
FT binding to human LOX-1."
FT /evidence="ECO:0000269|PubMed:30327444"
FT MUTAGEN 33
FT /note="A->I: Nearly complete loss of binding to human LOX-
FT 1."
FT /evidence="ECO:0000269|PubMed:30327444"
FT MUTAGEN 42
FT /note="Y->A: Nearly complete loss of binding to human LOX-
FT 1."
FT /evidence="ECO:0000269|PubMed:30327444"
FT MUTAGEN 43..70
FT /note="Missing: No longer adheres to human epithelial
FT cells, oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:15660996"
FT MUTAGEN 71..83
FT /note="Missing: No longer adheres to human epithelial
FT cells, oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:15660996"
FT MUTAGEN 88..150
FT /note="Missing: No longer adheres to human epithelial
FT cells, oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:20971901"
FT MUTAGEN 180..218
FT /note="Missing: Adheres to human epithelial cells,
FT oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:20971901"
FT MUTAGEN 219..288
FT /note="Missing: Adheres to human epithelial cells,
FT oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:20971901"
FT MUTAGEN 270..315
FT /note="Missing: Adheres to human epithelial cells,
FT oligomerizes on cell surface."
FT /evidence="ECO:0000269|PubMed:20971901"
FT MUTAGEN 351..405
FT /note="Missing: No longer surface-exposed, protein is in
FT periplasm and supernatant."
FT /evidence="ECO:0000269|PubMed:15660996"
SQ SEQUENCE 405 AA; 42549 MW; DE68E4FFA93AE288 CRC64;
MKHFPSKVLT TAILATFCSG ALAATNDDDV KKAATVAIAA AYNNGQEING FKAGETIYDI
DEDGTITKKD ATAADVEADD FKGLGLKKVV TNLTKTVNEN KQNVDAKVKA AESEIEKLTT
KLADTDAALA DTDAALDATT NALNKLGENI TTFAEETKTN IVKIDEKLEA VADTVDKHAE
AFNDIADSLD ETNTKADEAV KTANEAKQTA EETKQNVDAK VKAAETAAGK AEAAAGTANT
AADKAEAVAA KVTDIKADIA TNKDNIAKKA NSADVYTREE SDSKFVRIDG LNATTEKLDT
RLASAEKSIA DHDTRLNGLD KTVSDLRKET RQGLAEQAAL SGLFQPYNVG RFNVTAAVGG
YKSESAVAIG TGFRFTENFA AKAGVAVGTS SGSSAAYHVG VNYEW
