TCDA_CLODI
ID TCDA_CLODI Reviewed; 2710 AA.
AC P16154; M4NKU2;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 2.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Toxin A {ECO:0000303|PubMed:2109310};
DE EC=3.4.22.- {ECO:0000269|PubMed:17334356, ECO:0000269|PubMed:19553670, ECO:0000269|PubMed:27571750};
DE Contains:
DE RecName: Full=Glucosyltransferase TcdA {ECO:0000305};
DE EC=2.4.1.- {ECO:0000269|PubMed:22267739, ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:24905543, ECO:0000269|PubMed:30622517, ECO:0000269|PubMed:7775453};
GN Name=tcdA {ECO:0000303|PubMed:24958798};
GN Synonyms=toxA {ECO:0000303|PubMed:2109310};
OS Clostridioides difficile (Peptoclostridium difficile).
OC Bacteria; Firmicutes; Clostridia; Eubacteriales; Peptostreptococcaceae;
OC Clostridioides.
OX NCBI_TaxID=1496;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=2109310; DOI=10.1093/nar/18.6.1629;
RA Sauerborn M., von Eichel-Streiber C.;
RT "Nucleotide sequence of Clostridium difficile toxin A.";
RL Nucleic Acids Res. 18:1629-1630(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=2105276; DOI=10.1128/iai.58.2.480-488.1990;
RA Dove C.H., Wang S.-Z., Price S.B., Phelps C.J., Lyerly D.M., Wilkins T.D.,
RA Johnson J.L.;
RT "Molecular characterization of the Clostridium difficile toxin A gene.";
RL Infect. Immun. 58:480-488(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=24958798; DOI=10.1128/jcm.03487-13;
RA Du P., Cao B., Wang J., Li W., Jia H., Zhang W., Lu J., Li Z., Yu H.,
RA Chen C., Cheng Y.;
RT "Sequence variation in tcdA and tcdB of Clostridium difficile: ST37 with
RT truncated tcdA is a potential epidemic strain in China.";
RL J. Clin. Microbiol. 52:3264-3270(2014).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 4325 / VPI 10463;
RA von Eichel-Streiber C.;
RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION (TOXIN A).
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=1670930; DOI=10.1128/iai.59.1.73-78.1991;
RA Tucker K.D., Wilkins T.D.;
RT "Toxin A of Clostridium difficile binds to the human carbohydrate antigens
RT I, X, and Y.";
RL Infect. Immun. 59:73-78(1991).
RN [6]
RP FUNCTION (GLUCOSYLTRANSFERASE TCDA), AND CATALYTIC ACTIVITY
RP (GLUCOSYLTRANSFERASE TCDA).
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=7775453; DOI=10.1074/jbc.270.23.13932;
RA Just I., Wilm M., Selzer J., Rex G., von Eichel-Streiber C., Mann M.,
RA Aktories K.;
RT "The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho
RT proteins.";
RL J. Biol. Chem. 270:13932-13936(1995).
RN [7]
RP FUNCTION (TOXIN A), PROTEOLYTIC CLEAVAGE (TOXIN A), AND ACTIVITY REGULATION
RP (TOXIN A).
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=17334356; DOI=10.1038/nature05622;
RA Reineke J., Tenzer S., Rupnik M., Koschinski A., Hasselmayer O.,
RA Schrattenholz A., Schild H., von Eichel-Streiber C.;
RT "Autocatalytic cleavage of Clostridium difficile toxin B.";
RL Nature 446:415-419(2007).
RN [8]
RP CAUTION.
RX PubMed=18411291; DOI=10.1128/iai.00326-08;
RA Na X., Kim H., Moyer M.P., Pothoulakis C., LaMont J.T.;
RT "gp96 is a human colonocyte plasma membrane binding protein for Clostridium
RT difficile toxin A.";
RL Infect. Immun. 76:2862-2871(2008).
RN [9]
RP FUNCTION.
RC STRAIN=630 / Type X;
RX PubMed=19252482; DOI=10.1038/nature07822;
RA Lyras D., O'Connor J.R., Howarth P.M., Sambol S.P., Carter G.P.,
RA Phumoonna T., Poon R., Adams V., Vedantam G., Johnson S., Gerding D.N.,
RA Rood J.I.;
RT "Toxin B is essential for virulence of Clostridium difficile.";
RL Nature 458:1176-1179(2009).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=630 / Type X;
RX PubMed=20844489; DOI=10.1038/nature09397;
RA Kuehne S.A., Cartman S.T., Heap J.T., Kelly M.L., Cockayne A., Minton N.P.;
RT "The role of toxin A and toxin B in Clostridium difficile infection.";
RL Nature 467:711-713(2010).
RN [11]
RP SUBCELLULAR LOCATION (TOXIN A).
RX PubMed=20498856; DOI=10.1371/journal.pone.0010673;
RA Papatheodorou P., Zamboglou C., Genisyuerek S., Guttenberg G., Aktories K.;
RT "Clostridial glucosylating toxins enter cells via clathrin-mediated
RT endocytosis.";
RL PLoS ONE 5:e10673-e10673(2010).
RN [12]
RP SUBCELLULAR LOCATION (TOXIN A).
RC STRAIN=630 / Type X;
RX PubMed=22685398; DOI=10.1371/journal.ppat.1002727;
RA Govind R., Dupuy B.;
RT "Secretion of Clostridium difficile toxins A and B requires the holin-like
RT protein TcdE.";
RL PLoS Pathog. 8:e1002727-e1002727(2012).
RN [13]
RP FUNCTION (GLUCOSYLTRANSFERASE TCDA), AND CATALYTIC ACTIVITY
RP (GLUCOSYLTRANSFERASE TCDA).
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=24905543; DOI=10.1111/cmi.12321;
RA Genth H., Pauillac S., Schelle I., Bouvet P., Bouchier C.,
RA Varela-Chavez C., Just I., Popoff M.R.;
RT "Haemorrhagic toxin and lethal toxin from Clostridium sordellii strain
RT vpi9048: molecular characterization and comparative analysis of substrate
RT specificity of the large clostridial glucosylating toxins.";
RL Cell. Microbiol. 16:1706-1721(2014).
RN [14]
RP DOMAIN.
RX PubMed=25882477; DOI=10.1111/cmi.12449;
RA Varela Chavez C., Hoos S., Haustant G.M., Chenal A., England P.,
RA Blondel A., Pauillac S., Lacy D.B., Popoff M.R.;
RT "The catalytic domains of Clostridium sordellii lethal toxin and related
RT large clostridial glucosylating toxins specifically recognize the
RT negatively charged phospholipids phosphatidylserine and phosphatidic
RT acid.";
RL Cell. Microbiol. 17:1477-1493(2015).
RN [15]
RP FUNCTION (TOXIN A).
RX PubMed=27680706; DOI=10.1038/nature19799;
RA Tao L., Zhang J., Meraner P., Tovaglieri A., Wu X., Gerhard R., Zhang X.,
RA Stallcup W.B., Miao J., He X., Hurdle J.G., Breault D.T., Brass A.L.,
RA Dong M.;
RT "Frizzled proteins are colonic epithelial receptors for C. difficile toxin
RT B.";
RL Nature 538:350-355(2016).
RN [16]
RP FUNCTION (GLUCOSYLTRANSFERASE TCDA), AND CATALYTIC ACTIVITY
RP (GLUCOSYLTRANSFERASE TCDA).
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=30622517; DOI=10.3389/fmicb.2018.03078;
RA Genth H., Junemann J., Laemmerhirt C.M., Luecke A.C., Schelle I., Just I.,
RA Gerhard R., Pich A.;
RT "Difference in mono-O-glucosylation of Ras subtype GTPases between toxin A
RT and toxin B from Clostridioides difficile strain 10463 and lethal toxin
RT from Clostridium sordellii strain 6018.";
RL Front. Microbiol. 9:3078-3078(2018).
RN [17]
RP REVIEW.
RX PubMed=29146177; DOI=10.1016/j.toxicon.2017.11.003;
RA Popoff M.R.;
RT "Clostridium difficile and Clostridium sordellii toxins, proinflammatory
RT versus anti-inflammatory response.";
RL Toxicon 149:54-64(2018).
RN [18]
RP FUNCTION (TOXIN A), AND INTERACTION WITH HOST LDLR.
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=31160825; DOI=10.1038/s41564-019-0464-z;
RA Tao L., Tian S., Zhang J., Liu Z., Robinson-McCarthy L., Miyashita S.I.,
RA Breault D.T., Gerhard R., Oottamasathien S., Whelan S.P.J., Dong M.;
RT "Sulfated glycosaminoglycans and low-density lipoprotein receptor
RT contribute to Clostridium difficile toxin A entry into cells.";
RL Nat. Microbiol. 4:1760-1769(2019).
RN [19] {ECO:0007744|PDB:2F6E}
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 2583-2709.
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=16344467; DOI=10.1073/pnas.0506391102;
RA Ho J.G., Greco A., Rupnik M., Ng K.K.;
RT "Crystal structure of receptor-binding C-terminal repeats from Clostridium
RT difficile toxin A.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:18373-18378(2005).
RN [20] {ECO:0007744|PDB:2G7C}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 2456-2710 IN COMPLEX WITH
RP N-LINKED CARBOHYDRATE, FUNCTION (TOXIN A), AND DOMAIN (TOXIN A).
RC STRAIN=48489;
RX PubMed=16622409; DOI=10.1038/nsmb1084;
RA Greco A., Ho J.G., Lin S.J., Palcic M.M., Rupnik M., Ng K.K.;
RT "Carbohydrate recognition by Clostridium difficile toxin A.";
RL Nat. Struct. Mol. Biol. 13:460-461(2006).
RN [21] {ECO:0007744|PDB:3HO6}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 543-809 IN COMPLEX WITH
RP 1D-MYO-INOSITOL HEXAKISPHOSPHATE, FUNCTION (TOXIN A), PROTEOLYTIC CLEAVAGE
RP (TOXIN A), ACTIVE SITES (PROTEASE ACTIVITY), ACTIVITY REGULATION (TOXIN A),
RP AND MUTAGENESIS OF LEU-542; ASP-589; ASP-590; HIS-655 AND CYS-700.
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=19553670; DOI=10.1074/jbc.m109.018929;
RA Pruitt R.N., Chagot B., Cover M., Chazin W.J., Spiller B., Lacy D.B.;
RT "Structure-function analysis of inositol hexakisphosphate-induced
RT autoprocessing in Clostridium difficile toxin A.";
RL J. Biol. Chem. 284:21934-21940(2009).
RN [22] {ECO:0007744|PDB:4DMV, ECO:0007744|PDB:4DMW}
RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 1-541 IN COMPLEX WITH UDP AND
RP MANGANESE, COFACTOR, FUNCTION (GLUCOSYLTRANSFERASE TCDA), CATALYTIC
RP ACTIVITY (GLUCOSYLTRANSFERASE TCDA), AND BIOPHYSICOCHEMICAL PROPERTIES
RP (GLUCOSYLTRANSFERASE TCDA).
RC STRAIN=630 / Type X;
RX PubMed=22747490; DOI=10.1111/j.1742-4658.2012.08688.x;
RA D'Urzo N., Malito E., Biancucci M., Bottomley M.J., Maione D.,
RA Scarselli M., Martinelli M.;
RT "The structure of Clostridium difficile toxin A glucosyltransferase domain
RT bound to Mn2+ and UDP provides insights into glucosyltransferase activity
RT and product release.";
RL FEBS J. 279:3085-3097(2012).
RN [23] {ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:3SS1}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1-542 IN COMPLEX WITH
RP UDP-ALPHA-D-GLUCOSE AND MANGANESE, FUNCTION (GLUCOSYLTRANSFERASE TCDA),
RP CATALYTIC ACTIVITY (GLUCOSYLTRANSFERASE TCDA), PROTEOLYTIC CLEAVAGE (TOXIN
RP A), AND COFACTOR.
RX PubMed=22267739; DOI=10.1074/jbc.m111.298414;
RA Pruitt R.N., Chumbler N.M., Rutherford S.A., Farrow M.A., Friedman D.B.,
RA Spiller B., Lacy D.B.;
RT "Structural determinants of Clostridium difficile toxin A
RT glucosyltransferase activity.";
RL J. Biol. Chem. 287:8013-8020(2012).
RN [24] {ECO:0007744|PDB:4NBX, ECO:0007744|PDB:4NBZ}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 2573-2709.
RX PubMed=24311789; DOI=10.1074/jbc.m113.505917;
RA Murase T., Eugenio L., Schorr M., Hussack G., Tanha J., Kitova E.N.,
RA Klassen J.S., Ng K.K.;
RT "Structural basis for antibody recognition in the receptor-binding domains
RT of toxins A and B from Clostridium difficile.";
RL J. Biol. Chem. 289:2331-2343(2014).
RN [25] {ECO:0007744|PDB:4R04}
RP X-RAY CRYSTALLOGRAPHY (3.26 ANGSTROMS) OF 1-1832 IN COMPLEX WITH ZINC,
RP FUNCTION (TOXIN A), COFACTOR, ACTIVE SITES, AND MUTAGENESIS OF HIS-655;
RP CYS-700 AND HIS-759.
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=27571750; DOI=10.1038/nmicrobiol.2015.2;
RA Chumbler N.M., Rutherford S.A., Zhang Z., Farrow M.A., Lisher J.P.,
RA Farquhar E., Giedroc D.P., Spiller B.W., Melnyk R.A., Lacy D.B.;
RT "Crystal structure of Clostridium difficile toxin A.";
RL Nat. Microbiol. 1:15002-15002(2016).
RN [26] {ECO:0007744|PDB:5UMI}
RP X-RAY CRYSTALLOGRAPHY (3.23 ANGSTROMS) OF 2461-2710.
RX PubMed=28705932; DOI=10.1074/jbc.m117.781112;
RA Kroh H.K., Chandrasekaran R., Rosenthal K., Woods R., Jin X., Ohi M.D.,
RA Nyborg A.C., Rainey G.J., Warrener P., Spiller B.W., Lacy D.B.;
RT "Use of a neutralizing antibody helps identify structural features critical
RT for binding of Clostridium difficile toxin TcdA to the host cell surface.";
RL J. Biol. Chem. 292:14401-14412(2017).
RN [27] {ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL}
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 1-544 IN COMPLEX WITH
RP UDP-ALPHA-D-GLUCOSE AND MANGANESE, AND COFACTOR.
RC STRAIN=ATCC 4325 / VPI 10463;
RX PubMed=28433497; DOI=10.1016/j.jsb.2017.04.006;
RA Alvin J.W., Lacy D.B.;
RT "Clostridium difficile toxin glucosyltransferase domains in complex with a
RT non-hydrolyzable UDP-glucose analogue.";
RL J. Struct. Biol. 198:203-209(2017).
CC -!- FUNCTION: [Toxin A]: Precursor of a cytotoxin that targets and disrupts
CC the colonic epithelium, inducing the host inflammatory and innate
CC immune responses and resulting in diarrhea and pseudomembranous colitis
CC (PubMed:20844489). TcdA and TcdB constitute the main toxins that
CC mediate the pathology of C.difficile infection, an opportunistic
CC pathogen that colonizes the colon when the normal gut microbiome is
CC disrupted (PubMed:19252482, PubMed:20844489). Compared to TcdB, TcdA is
CC less virulent and less important for inducing the host inflammatory and
CC innate immune responses (PubMed:19252482). This form constitutes the
CC precursor of the toxin: it enters into host cells and mediates
CC autoprocessing to release the active toxin (Glucosyltransferase TcdA)
CC into the host cytosol (By similarity). Targets colonic epithelia by
CC binding to some receptor, and enters host cells via clathrin-mediated
CC endocytosis (By similarity). Binding to LDLR, as well as carbohydrates
CC and sulfated glycosaminoglycans on host cell surface contribute to
CC entry into cells (PubMed:1670930, PubMed:31160825, PubMed:16622409). In
CC contrast to TcdB, Frizzled receptors FZD1, FZD2 and FZD7 do not act as
CC host receptors in the colonic epithelium for TcdA (PubMed:27680706).
CC Once entered into host cells, acidification in the endosome promotes
CC the membrane insertion of the translocation region and formation of a
CC pore, leading to translocation of the GT44 and peptidase C80 domains
CC across the endosomal membrane (By similarity). This activates the
CC peptidase C80 domain and autocatalytic processing, releasing the N-
CC terminal part (Glucosyltransferase TcdA), which constitutes the active
CC part of the toxin, in the cytosol (PubMed:17334356, PubMed:19553670,
CC PubMed:27571750). {ECO:0000250|UniProtKB:P18177,
CC ECO:0000269|PubMed:16622409, ECO:0000269|PubMed:1670930,
CC ECO:0000269|PubMed:17334356, ECO:0000269|PubMed:19252482,
CC ECO:0000269|PubMed:19553670, ECO:0000269|PubMed:20844489,
CC ECO:0000269|PubMed:27571750, ECO:0000269|PubMed:27680706,
CC ECO:0000269|PubMed:31160825}.
CC -!- FUNCTION: [Glucosyltransferase TcdA]: Active form of the toxin, which
CC is released into the host cytosol following autoprocessing and
CC inactivates small GTPases (PubMed:7775453, PubMed:24905543,
CC PubMed:30622517, PubMed:22747490, PubMed:22267739). Acts by mediating
CC monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB,
CC RhoC, Rap2A and Cdc42) in host cells at the conserved threonine residue
CC located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose
CC as the sugar donor (PubMed:7775453, PubMed:24905543, PubMed:30622517,
CC PubMed:22747490, PubMed:22267739). Monoglucosylation of host small
CC GTPases completely prevents the recognition of the downstream effector,
CC blocking the GTPases in their inactive form, leading to actin
CC cytoskeleton disruption and cell death, resulting in the loss of
CC colonic epithelial barrier function (PubMed:7775453). Also able to
CC catalyze monoglucosylation of some members of the Ras family (H-
CC Ras/HRAS, K-Ras/KRAS and N-Ras/NRAS), but with much less efficiency
CC than with Rho proteins, suggesting that it does not act on Ras proteins
CC in vivo (PubMed:30622517). {ECO:0000269|PubMed:22267739,
CC ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:24905543,
CC ECO:0000269|PubMed:30622517, ECO:0000269|PubMed:7775453}.
CC -!- CATALYTIC ACTIVITY: [Glucosyltransferase TcdA]:
CC Reaction=L-threonyl-[protein] + UDP-alpha-D-glucose = 3-O-(alpha-D-
CC glucosyl)-L-threonyl-[protein] + H(+) + UDP; Xref=Rhea:RHEA:64684,
CC Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:16656, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30013, ChEBI:CHEBI:58223, ChEBI:CHEBI:58885,
CC ChEBI:CHEBI:156085; Evidence={ECO:0000269|PubMed:22267739,
CC ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:24905543,
CC ECO:0000269|PubMed:30622517, ECO:0000269|PubMed:7775453};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64685;
CC Evidence={ECO:0000269|PubMed:22267739, ECO:0000269|PubMed:22747490,
CC ECO:0000269|PubMed:24905543, ECO:0000269|PubMed:30622517,
CC ECO:0000269|PubMed:7775453};
CC -!- COFACTOR: [Toxin A]:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:27571750};
CC Note=Binds 1 Zn(2+) ion per subunit (PubMed:27571750). Zn(2+) is
CC required for autocatalytic cleavage (PubMed:27571750).
CC {ECO:0000269|PubMed:27571750};
CC -!- COFACTOR: [Glucosyltransferase TcdA]:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:22267739, ECO:0000269|PubMed:22747490,
CC ECO:0000269|PubMed:28433497};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P18177};
CC Note=Has higher activity with Mn(2+), but most likely uses Mg(2+) in
CC host cells (By similarity). Required for glucosyltransferase activity
CC (PubMed:22747490). {ECO:0000250|UniProtKB:P18177,
CC ECO:0000269|PubMed:22747490};
CC -!- ACTIVITY REGULATION: [Toxin A]: Protease activity is activated upon
CC binding to 1D-myo-inositol hexakisphosphate (InsP6), which induces
CC conformational reorganization. {ECO:0000269|PubMed:17334356,
CC ECO:0000269|PubMed:19553670}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Glucosyltransferase TcdA]:
CC Kinetic parameters:
CC KM=43.9 uM for UDP-alpha-D-glucose (in presence of K(+))
CC {ECO:0000269|PubMed:22747490};
CC KM=36.3 uM for UDP-alpha-D-glucose (in presence of NH4(+))
CC {ECO:0000269|PubMed:22747490};
CC KM=51.1 uM for UDP-alpha-D-glucose (in presence of Na(+))
CC {ECO:0000269|PubMed:22747490};
CC Vmax=252.2 pmol/min/ug enzyme with UDP-alpha-D-glucose (in presence
CC of K(+)) {ECO:0000269|PubMed:22747490};
CC Vmax=162.8 pmol/min/ug enzyme with UDP-alpha-D-glucose (in presence
CC of NH4(+)) {ECO:0000269|PubMed:22747490};
CC Vmax=36.4 pmol/min/ug enzyme with UDP-alpha-D-glucose (in presence of
CC Na(+)) {ECO:0000269|PubMed:22747490};
CC -!- SUBUNIT: [Toxin A]: Interacts with host LDLR; LDLR probably does not
CC constitute a major receptor but may contribute to entry into cells.
CC {ECO:0000269|PubMed:31160825}.
CC -!- SUBCELLULAR LOCATION: [Toxin A]: Secreted
CC {ECO:0000269|PubMed:22685398}. Host endosome membrane
CC {ECO:0000250|UniProtKB:P18177}. Note=Secreted from C.difficile cell
CC into the extracellular environment via help of holin-like protein
CC TcdE/UtxA (PubMed:22685398). Binds to the cell surface receptors via
CC the receptor-binding region and enters the cells via clathrin-mediated
CC endocytosis (PubMed:20498856). Acidification in the endosome triggers
CC conformational changes that promote the membrane insertion of the
CC translocation region, allowing formation of a pore, leading to
CC translocation of the GT44 and peptidase C80 domains across the
CC endosomal membrane (By similarity). 1D-myo-inositol hexakisphosphate-
CC binding (InsP6) activates the peptidase C80 domain and autoprocessing,
CC generating the Glucosyltransferase TcdA form, which is released in the
CC host cytosol (PubMed:19553670). {ECO:0000250|UniProtKB:P18177,
CC ECO:0000269|PubMed:19553670, ECO:0000269|PubMed:20498856,
CC ECO:0000269|PubMed:22685398}.
CC -!- SUBCELLULAR LOCATION: [Glucosyltransferase TcdA]: Host cytoplasm, host
CC cytosol {ECO:0000250|UniProtKB:P18177}. Host cell membrane
CC {ECO:0000250|UniProtKB:Q46342}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q46342}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q46342}. Note=Binding to phospholipids, such as
CC phosphatidylserine and phosphatidic acid promotes localization to the
CC inner face of the cell membrane close to its membrane anchored
CC substrates (small GTPases). {ECO:0000250|UniProtKB:Q46342}.
CC -!- DOMAIN: [Toxin A]: Consists of 4 functional domains: (1) the N-terminal
CC GT44 domain (glucosyltransferase, also named GTD), which mediates
CC glucosylation of host small GTPases, (2) an autoprocessing region that
CC catalyzes autoprocessing to release the N-terminal GT44 domain in the
CC host cytosol, (3) the translocation region that forms a pore to promote
CC translocation of the GT44 and peptidase C80 domains across the
CC endosomal membrane and (4) the receptor-binding (CROPS) region that
CC mediates binding to host cells and contribute to entry into cells.
CC {ECO:0000303|PubMed:29146177}.
CC -!- DOMAIN: [Toxin A]: The receptor-binding (CROPS) region is dynamic and
CC can have open and closed conformations depending of the pH: has an open
CC conformation at endosomal pH and a closed conformation at neutral pH.
CC {ECO:0000250|UniProtKB:P18177}.
CC -!- DOMAIN: [Toxin A]: The cell wall-binding repeats bind carbohydrates,
CC such as Galalpha1-3Galbeta1-4GlcNAc, probably contributing to entry
CC into cells. {ECO:0000269|PubMed:16622409, ECO:0000305|PubMed:1670930}.
CC -!- DOMAIN: [Glucosyltransferase TcdA]: The four-helical bundle region
CC mediates binding to phospholipids, such as phosphatidylserine and
CC phosphatidic acid (PubMed:25882477). This promotes localization to the
CC inner face of the cell membrane close to small GTPases (By similarity).
CC {ECO:0000250|UniProtKB:Q46342, ECO:0000269|PubMed:25882477}.
CC -!- PTM: [Toxin A]: Undergoes autocatalytic cleavage to release the N-
CC terminal part (Glucosyltransferase TcdA), which constitutes the active
CC part of the toxin, in the host cytosol (PubMed:17334356,
CC PubMed:22267739, PubMed:19553670, PubMed:27571750). 1D-myo-inositol
CC hexakisphosphate-binding (InsP6) activates the peptidase C80 domain and
CC promotes autoprocessing (PubMed:17334356, PubMed:19553670).
CC {ECO:0000269|PubMed:17334356, ECO:0000269|PubMed:19553670,
CC ECO:0000269|PubMed:22267739, ECO:0000269|PubMed:27571750}.
CC -!- DISRUPTION PHENOTYPE: Cells lacking tcdA display virulence and
CC cytotoxity, because of the presence of TcdB (PubMed:20844489). Cells
CC lacking both tcdA and tcdB display a strongly reduced virulence
CC (PubMed:20844489). {ECO:0000269|PubMed:20844489}.
CC -!- SIMILARITY: Belongs to the clostridial glucosylating toxin (LCGT)
CC family. {ECO:0000305}.
CC -!- CAUTION: Host HSP90B1/gp96 was initially identified as a possible
CC receptor for TcdA (PubMed:18411291). However, as HSP90B1/gp96 localizes
CC in the endoplasmic reticulum and not at the cell membrane, it probably
CC does not act as a receptor for TcdA. {ECO:0000269|PubMed:18411291,
CC ECO:0000305}.
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DR EMBL; X51797; CAA36094.1; -; Genomic_DNA.
DR EMBL; M30307; AAA23283.1; -; Genomic_DNA.
DR EMBL; KC292122; AGG91568.1; -; Genomic_DNA.
DR EMBL; X92982; CAA63564.1; -; Genomic_DNA.
DR PIR; A37052; A37052.
DR RefSeq; WP_009902072.1; NZ_PZRE01000002.1.
DR PDB; 2F6E; X-ray; 1.85 A; A=2583-2709.
DR PDB; 2G7C; X-ray; 2.00 A; A/B=2456-2710.
DR PDB; 2QJ6; X-ray; 2.50 A; A/B=2387-2706.
DR PDB; 3HO6; X-ray; 1.60 A; A/B=543-809.
DR PDB; 3SRZ; X-ray; 2.58 A; A=1-542.
DR PDB; 3SS1; X-ray; 2.20 A; A=1-542.
DR PDB; 4DMV; X-ray; 1.50 A; A=1-541.
DR PDB; 4DMW; X-ray; 2.50 A; A=1-541.
DR PDB; 4NBX; X-ray; 1.75 A; A=2573-2709.
DR PDB; 4NBZ; X-ray; 1.75 A; A/C=2573-2709.
DR PDB; 4R04; X-ray; 3.26 A; A=1-1832.
DR PDB; 5UMI; X-ray; 3.23 A; C=2461-2710.
DR PDB; 5UQK; X-ray; 1.85 A; A=1-544.
DR PDB; 5UQL; X-ray; 1.97 A; A=1-544.
DR PDB; 7U1Z; X-ray; 3.18 A; A/B=843-2481.
DR PDBsum; 2F6E; -.
DR PDBsum; 2G7C; -.
DR PDBsum; 2QJ6; -.
DR PDBsum; 3HO6; -.
DR PDBsum; 3SRZ; -.
DR PDBsum; 3SS1; -.
DR PDBsum; 4DMV; -.
DR PDBsum; 4DMW; -.
DR PDBsum; 4NBX; -.
DR PDBsum; 4NBZ; -.
DR PDBsum; 4R04; -.
DR PDBsum; 5UMI; -.
DR PDBsum; 5UQK; -.
DR PDBsum; 5UQL; -.
DR PDBsum; 7U1Z; -.
DR SMR; P16154; -.
DR BindingDB; P16154; -.
DR ChEMBL; CHEMBL3580504; -.
DR CAZy; GT44; Glycosyltransferase Family 44.
DR MEROPS; C80.002; -.
DR TCDB; 1.C.57.1.2; the clostridial cytotoxin (cct) family.
DR UniLectin; P16154; -.
DR PRIDE; P16154; -.
DR ABCD; P16154; 2 sequenced antibodies.
DR EnsemblBacteria; PBG26087; PBG26087; BGU81_11750.
DR BRENDA; 2.4.1.B62; 1473.
DR BRENDA; 3.1.4.B4; 1473.
DR EvolutionaryTrace; P16154; -.
DR PHI-base; PHI:9028; -.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0044164; C:host cell cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0044175; C:host cell endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0016757; F:glycosyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0000822; F:inositol hexakisphosphate binding; IDA:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0035251; F:UDP-glucosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0044083; P:modulation by symbiont of host Rho protein signal transduction; IDA:UniProtKB.
DR GO; GO:0034260; P:negative regulation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0030836; P:positive regulation of actin filament depolymerization; IDA:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB.
DR GO; GO:0018243; P:protein O-linked glycosylation via threonine; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.11050; -; 1.
DR InterPro; IPR018337; Cell_wall/Cho-bd_repeat.
DR InterPro; IPR020974; CPD_dom.
DR InterPro; IPR038383; CPD_dom_sf.
DR InterPro; IPR029044; Nucleotide-diphossugar_trans.
DR InterPro; IPR024770; TcdA/TcdB_cat.
DR InterPro; IPR024772; TcdA/TcdB_N.
DR InterPro; IPR024769; TcdA/TcdB_pore_forming.
DR Pfam; PF01473; Choline_bind_1; 5.
DR Pfam; PF19127; Choline_bind_3; 5.
DR Pfam; PF11713; Peptidase_C80; 1.
DR Pfam; PF12919; TcdA_TcdB; 1.
DR Pfam; PF12920; TcdA_TcdB_pore; 1.
DR Pfam; PF12918; TcdB_N; 1.
DR SUPFAM; SSF53448; SSF53448; 1.
DR PROSITE; PS51771; CGT_MARTX_CPD; 1.
DR PROSITE; PS51170; CW; 32.
PE 1: Evidence at protein level;
KW 3D-structure; Autocatalytic cleavage; Enterotoxin; Glycosyltransferase;
KW Host cell membrane; Host cytoplasm; Host endosome; Host membrane;
KW Hydrolase; Lipid-binding; Magnesium; Manganese; Membrane; Metal-binding;
KW Protease; Repeat; Secreted; Thiol protease; Toxin; Transferase; Virulence;
KW Zinc.
FT CHAIN 1..2710
FT /note="Toxin A"
FT /id="PRO_0000072634"
FT CHAIN 1..542
FT /note="Glucosyltransferase TcdA"
FT /evidence="ECO:0000305|PubMed:19553670"
FT /id="PRO_0000451191"
FT DOMAIN 95..467
FT /note="GT44"
FT /evidence="ECO:0000255"
FT DOMAIN 569..776
FT /note="Peptidase C80"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01107"
FT REPEAT 1810..1829
FT /note="Cell wall-binding 1"
FT REPEAT 1851..1870
FT /note="Cell wall-binding 2"
FT REPEAT 1872..1891
FT /note="Cell wall-binding 3"
FT REPEAT 1923..1942
FT /note="Cell wall-binding 4"
FT REPEAT 1943..1962
FT /note="Cell wall-binding 5"
FT REPEAT 1964..1983
FT /note="Cell wall-binding 6"
FT REPEAT 1985..2004
FT /note="Cell wall-binding 7"
FT REPEAT 2006..2025
FT /note="Cell wall-binding 8"
FT REPEAT 2057..2076
FT /note="Cell wall-binding 9"
FT REPEAT 2077..2096
FT /note="Cell wall-binding 10"
FT REPEAT 2098..2117
FT /note="Cell wall-binding 11"
FT REPEAT 2119..2138
FT /note="Cell wall-binding 12"
FT REPEAT 2140..2159
FT /note="Cell wall-binding 13"
FT REPEAT 2191..2210
FT /note="Cell wall-binding 14"
FT REPEAT 2211..2230
FT /note="Cell wall-binding 15"
FT REPEAT 2232..2251
FT /note="Cell wall-binding 16"
FT REPEAT 2252..2271
FT /note="Cell wall-binding 17"
FT REPEAT 2305..2324
FT /note="Cell wall-binding 18"
FT REPEAT 2325..2344
FT /note="Cell wall-binding 19"
FT REPEAT 2346..2365
FT /note="Cell wall-binding 20"
FT REPEAT 2367..2386
FT /note="Cell wall-binding 21"
FT REPEAT 2388..2407
FT /note="Cell wall-binding 22"
FT REPEAT 2439..2458
FT /note="Cell wall-binding 23"
FT REPEAT 2459..2478
FT /note="Cell wall-binding 24"
FT REPEAT 2480..2499
FT /note="Cell wall-binding 25"
FT REPEAT 2501..2520
FT /note="Cell wall-binding 26"
FT REPEAT 2552..2571
FT /note="Cell wall-binding 27"
FT REPEAT 2572..2591
FT /note="Cell wall-binding 28"
FT REPEAT 2593..2612
FT /note="Cell wall-binding 29"
FT REPEAT 2643..2662
FT /note="Cell wall-binding 30"
FT REPEAT 2663..2682
FT /note="Cell wall-binding 31"
FT REPEAT 2685..2704
FT /note="Cell wall-binding 32"
FT REGION 1..90
FT /note="Four-helical bundle"
FT /evidence="ECO:0000305|PubMed:25882477"
FT REGION 95..467
FT /note="Glucosyltransferase region"
FT /evidence="ECO:0000303|PubMed:29146177"
FT REGION 543..801
FT /note="Autoprocessing region"
FT /evidence="ECO:0000303|PubMed:29146177"
FT REGION 802..1497
FT /note="Translocation region"
FT /evidence="ECO:0000303|PubMed:29146177"
FT REGION 1832..2483
FT /note="Receptor-binding (CROPS) region"
FT /evidence="ECO:0000303|PubMed:29146177"
FT ACT_SITE 655
FT /note="For protease activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01107,
FT ECO:0000269|PubMed:19553670, ECO:0000269|PubMed:27571750"
FT ACT_SITE 700
FT /note="Nucleophile; for protease activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01107,
FT ECO:0000269|PubMed:19553670, ECO:0000269|PubMed:27571750"
FT BINDING 100..102
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:28433497,
FT ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:4DMV,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 138
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:28433497, ECO:0007744|PDB:3SRZ,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 268..272
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:28433497,
FT ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:4DMV,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 285..287
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:28433497,
FT ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:4DMV,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 285
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0007744|PDB:3SS1"
FT BINDING 287
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:28433497,
FT ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:3SS1,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 514
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:28433497,
FT ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:3SS1,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 517..519
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000269|PubMed:22267739,
FT ECO:0000269|PubMed:22747490, ECO:0000269|PubMed:28433497,
FT ECO:0007744|PDB:3SRZ, ECO:0007744|PDB:4DMV,
FT ECO:0007744|PDB:5UQK, ECO:0007744|PDB:5UQL"
FT BINDING 544
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:27571750,
FT ECO:0007744|PDB:4R04"
FT BINDING 545
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:27571750,
FT ECO:0007744|PDB:4R04"
FT BINDING 551
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 579
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 602
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 649
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 655
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:27571750,
FT ECO:0007744|PDB:4R04"
FT BINDING 753..754
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 759
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:27571750,
FT ECO:0007744|PDB:4R04"
FT BINDING 766
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 777
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 794
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0007744|PDB:3HO6"
FT BINDING 2540
FT /ligand="alpha-D-galactosyl-(1->3)-beta-D-galactosyl-
FT (1->4)-N-acetyl-beta-D-glucosamine"
FT /ligand_id="ChEBI:CHEBI:62327"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:16622409,
FT ECO:0007744|PDB:2G7C"
FT BINDING 2547..2550
FT /ligand="alpha-D-galactosyl-(1->3)-beta-D-galactosyl-
FT (1->4)-N-acetyl-beta-D-glucosamine"
FT /ligand_id="ChEBI:CHEBI:62327"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:16622409,
FT ECO:0007744|PDB:2G7C"
FT BINDING 2567..2570
FT /ligand="alpha-D-galactosyl-(1->3)-beta-D-galactosyl-
FT (1->4)-N-acetyl-beta-D-glucosamine"
FT /ligand_id="ChEBI:CHEBI:62327"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:16622409,
FT ECO:0007744|PDB:2G7C"
FT BINDING 2631
FT /ligand="alpha-D-galactosyl-(1->3)-beta-D-galactosyl-
FT (1->4)-N-acetyl-beta-D-glucosamine"
FT /ligand_id="ChEBI:CHEBI:62327"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:16622409,
FT ECO:0007744|PDB:2G7C"
FT BINDING 2638..2641
FT /ligand="alpha-D-galactosyl-(1->3)-beta-D-galactosyl-
FT (1->4)-N-acetyl-beta-D-glucosamine"
FT /ligand_id="ChEBI:CHEBI:62327"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:16622409,
FT ECO:0007744|PDB:2G7C"
FT BINDING 2658..2661
FT /ligand="alpha-D-galactosyl-(1->3)-beta-D-galactosyl-
FT (1->4)-N-acetyl-beta-D-glucosamine"
FT /ligand_id="ChEBI:CHEBI:62327"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:16622409,
FT ECO:0007744|PDB:2G7C"
FT SITE 542..543
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000305|PubMed:19553670"
FT MUTAGEN 542
FT /note="L->A: Abolished cleavage."
FT /evidence="ECO:0000269|PubMed:19553670"
FT MUTAGEN 589
FT /note="D->N: Abolished protease activity and
FT autoprocessing."
FT /evidence="ECO:0000269|PubMed:19553670"
FT MUTAGEN 590
FT /note="D->N: Does not affect protease activity and
FT autoprocessing."
FT /evidence="ECO:0000269|PubMed:19553670"
FT MUTAGEN 655
FT /note="H->A: Abolished protease activity and
FT autoprocessing."
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0000269|PubMed:27571750"
FT MUTAGEN 700
FT /note="C->A,S: Abolished protease activity and
FT autoprocessing."
FT /evidence="ECO:0000269|PubMed:19553670,
FT ECO:0000269|PubMed:27571750"
FT MUTAGEN 759
FT /note="H->A: Abolished autoprocessing."
FT /evidence="ECO:0000269|PubMed:27571750"
FT CONFLICT 2080
FT /note="L -> W (in Ref. 3; AGG91568)"
FT /evidence="ECO:0000305"
FT HELIX 6..12
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 21..34
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 41..61
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 68..88
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 95..100
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 108..120
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 121..123
FT /evidence="ECO:0007829|PDB:5UQK"
FT STRAND 124..130
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 137..160
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 167..192
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 194..197
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 201..212
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 217..232
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 233..235
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 236..238
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 239..243
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 248..258
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 259..261
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 264..279
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 281..284
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 294..299
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 308..323
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 325..328
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 334..336
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 339..350
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 355..357
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 366..368
FT /evidence="ECO:0007829|PDB:4DMW"
FT STRAND 373..377
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 380..388
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 393..417
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 418..420
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 423..435
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 440..442
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 443..449
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 452..454
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 455..457
FT /evidence="ECO:0007829|PDB:4DMV"
FT STRAND 458..460
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 464..467
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 470..482
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 494..497
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 498..500
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 504..506
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 512..517
FT /evidence="ECO:0007829|PDB:4DMV"
FT HELIX 523..536
FT /evidence="ECO:0007829|PDB:4DMV"
FT TURN 546..548
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 558..563
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 565..569
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 578..585
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 590..602
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 604..606
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 607..611
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 612..617
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 619..623
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 630..634
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 640..642
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 646..653
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 658..661
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 665..667
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 670..684
FT /evidence="ECO:0007829|PDB:3HO6"
FT TURN 685..687
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 691..701
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 709..711
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 713..728
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 734..736
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 737..741
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 746..748
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 754..757
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 761..764
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 766..771
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 778..783
FT /evidence="ECO:0007829|PDB:3HO6"
FT TURN 784..787
FT /evidence="ECO:0007829|PDB:3HO6"
FT STRAND 788..795
FT /evidence="ECO:0007829|PDB:3HO6"
FT HELIX 796..811
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 812..815
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 817..839
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 853..877
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 884..893
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 895..904
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 905..907
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 910..915
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 919..935
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 960..971
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 972..974
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 982..996
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1000..1002
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1006..1018
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1029..1031
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1043..1052
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1056..1066
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1075..1093
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 1100..1103
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1110..1114
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1116..1118
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1119..1134
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1137..1141
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 1142..1144
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1145..1148
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1154..1158
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 1159..1162
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1163..1166
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1169..1172
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1181..1185
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1196..1199
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1201..1203
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1204..1207
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1220..1223
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1230..1233
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1236..1238
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1248..1259
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 1261..1263
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1266..1276
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1279..1283
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1288..1291
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1297..1300
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1307..1311
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1314..1318
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1324..1327
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1334..1338
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1345..1348
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1350..1353
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1354..1359
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1362..1368
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1372..1375
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1380..1384
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1389..1394
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1403..1412
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1414..1420
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 1421..1424
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1425..1432
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1434..1451
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1456..1463
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1465..1467
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1469..1475
FT /evidence="ECO:0007829|PDB:4R04"
FT TURN 1476..1479
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1480..1487
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1490..1497
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1500..1506
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1511..1518
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1521..1529
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1530..1532
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1537..1544
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1546..1548
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1550..1557
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1559..1570
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1582..1589
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1591..1594
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1602..1613
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1615..1623
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1625..1627
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1629..1637
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1639..1646
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1653..1657
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1670..1675
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1676..1678
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1681..1684
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1688..1690
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1698..1702
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1714..1716
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1726..1732
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1737..1742
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1745..1754
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1757..1765
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1768..1770
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1772..1775
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1778..1781
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 1783..1785
FT /evidence="ECO:0007829|PDB:4R04"
FT HELIX 1790..1796
FT /evidence="ECO:0007829|PDB:4R04"
FT STRAND 2395..2397
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2399..2401
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2410..2412
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2424..2429
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2442..2445
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2448..2451
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2454..2457
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2462..2465
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2468..2472
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2474..2478
FT /evidence="ECO:0007829|PDB:2QJ6"
FT STRAND 2482..2486
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2489..2493
FT /evidence="ECO:0007829|PDB:2G7C"
FT TURN 2495..2497
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2503..2507
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2510..2514
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2523..2527
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2530..2534
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2539..2542
FT /evidence="ECO:0007829|PDB:5UMI"
FT STRAND 2553..2558
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2561..2565
FT /evidence="ECO:0007829|PDB:2G7C"
FT STRAND 2574..2578
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2581..2585
FT /evidence="ECO:0007829|PDB:4NBX"
FT TURN 2587..2589
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2590..2592
FT /evidence="ECO:0007829|PDB:4NBZ"
FT STRAND 2595..2599
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2602..2607
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2614..2618
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2621..2626
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2630..2633
FT /evidence="ECO:0007829|PDB:5UMI"
FT STRAND 2644..2649
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2652..2656
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2660..2662
FT /evidence="ECO:0007829|PDB:2F6E"
FT STRAND 2665..2669
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2672..2676
FT /evidence="ECO:0007829|PDB:4NBX"
FT TURN 2678..2680
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2686..2691
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2694..2698
FT /evidence="ECO:0007829|PDB:4NBX"
FT STRAND 2700..2702
FT /evidence="ECO:0007829|PDB:5UMI"
FT STRAND 2704..2707
FT /evidence="ECO:0007829|PDB:2G7C"
SQ SEQUENCE 2710 AA; 308056 MW; 0A6E52CE84C14421 CRC64;
MSLISKEELI KLAYSIRPRE NEYKTILTNL DEYNKLTTNN NENKYLQLKK LNESIDVFMN
KYKTSSRNRA LSNLKKDILK EVILIKNSNT SPVEKNLHFV WIGGEVSDIA LEYIKQWADI
NAEYNIKLWY DSEAFLVNTL KKAIVESSTT EALQLLEEEI QNPQFDNMKF YKKRMEFIYD
RQKRFINYYK SQINKPTVPT IDDIIKSHLV SEYNRDETVL ESYRTNSLRK INSNHGIDIR
ANSLFTEQEL LNIYSQELLN RGNLAAASDI VRLLALKNFG GVYLDVDMLP GIHSDLFKTI
SRPSSIGLDR WEMIKLEAIM KYKKYINNYT SENFDKLDQQ LKDNFKLIIE SKSEKSEIFS
KLENLNVSDL EIKIAFALGS VINQALISKQ GSYLTNLVIE QVKNRYQFLN QHLNPAIESD
NNFTDTTKIF HDSLFNSATA ENSMFLTKIA PYLQVGFMPE ARSTISLSGP GAYASAYYDF
INLQENTIEK TLKASDLIEF KFPENNLSQL TEQEINSLWS FDQASAKYQF EKYVRDYTGG
SLSEDNGVDF NKNTALDKNY LLNNKIPSNN VEEAGSKNYV HYIIQLQGDD ISYEATCNLF
SKNPKNSIII QRNMNESAKS YFLSDDGESI LELNKYRIPE RLKNKEKVKV TFIGHGKDEF
NTSEFARLSV DSLSNEISSF LDTIKLDISP KNVEVNLLGC NMFSYDFNVE ETYPGKLLLS
IMDKITSTLP DVNKNSITIG ANQYEVRINS EGRKELLAHS GKWINKEEAI MSDLSSKEYI
FFDSIDNKLK AKSKNIPGLA SISEDIKTLL LDASVSPDTK FILNNLKLNI ESSIGDYIYY
EKLEPVKNII HNSIDDLIDE FNLLENVSDE LYELKKLNNL DEKYLISFED ISKNNSTYSV
RFINKSNGES VYVETEKEIF SKYSEHITKE ISTIKNSIIT DVNGNLLDNI QLDHTSQVNT
LNAAFFIQSL IDYSSNKDVL NDLSTSVKVQ LYAQLFSTGL NTIYDSIQLV NLISNAVNDT
INVLPTITEG IPIVSTILDG INLGAAIKEL LDEHDPLLKK ELEAKVGVLA INMSLSIAAT
VASIVGIGAE VTIFLLPIAG ISAGIPSLVN NELILHDKAT SVVNYFNHLS ESKKYGPLKT
EDDKILVPID DLVISEIDFN NNSIKLGTCN ILAMEGGSGH TVTGNIDHFF SSPSISSHIP
SLSIYSAIGI ETENLDFSKK IMMLPNAPSR VFWWETGAVP GLRSLENDGT RLLDSIRDLY
PGKFYWRFYA FFDYAITTLK PVYEDTNIKI KLDKDTRNFI MPTITTNEIR NKLSYSFDGA
GGTYSLLLSS YPISTNINLS KDDLWIFNID NEVREISIEN GTIKKGKLIK DVLSKIDINK
NKLIIGNQTI DFSGDIDNKD RYIFLTCELD DKISLIIEIN LVAKSYSLLL SGDKNYLISN
LSNTIEKINT LGLDSKNIAY NYTDESNNKY FGAISKTSQK SIIHYKKDSK NILEFYNDST
LEFNSKDFIA EDINVFMKDD INTITGKYYV DNNTDKSIDF SISLVSKNQV KVNGLYLNES
VYSSYLDFVK NSDGHHNTSN FMNLFLDNIS FWKLFGFENI NFVIDKYFTL VGKTNLGYVE
FICDNNKNID IYFGEWKTSS SKSTIFSGNG RNVVVEPIYN PDTGEDISTS LDFSYEPLYG
IDRYINKVLI APDLYTSLIN INTNYYSNEY YPEIIVLNPN TFHKKVNINL DSSSFEYKWS
TEGSDFILVR YLEESNKKIL QKIRIKGILS NTQSFNKMSI DFKDIKKLSL GYIMSNFKSF
NSENELDRDH LGFKIIDNKT YYYDEDSKLV KGLININNSL FYFDPIEFNL VTGWQTINGK
KYYFDINTGA ALTSYKIING KHFYFNNDGV MQLGVFKGPD GFEYFAPANT QNNNIEGQAI
VYQSKFLTLN GKKYYFDNNS KAVTGWRIIN NEKYYFNPNN AIAAVGLQVI DNNKYYFNPD
TAIISKGWQT VNGSRYYFDT DTAIAFNGYK TIDGKHFYFD SDCVVKIGVF STSNGFEYFA
PANTYNNNIE GQAIVYQSKF LTLNGKKYYF DNNSKAVTGL QTIDSKKYYF NTNTAEAATG
WQTIDGKKYY FNTNTAEAAT GWQTIDGKKY YFNTNTAIAS TGYTIINGKH FYFNTDGIMQ
IGVFKGPNGF EYFAPANTDA NNIEGQAILY QNEFLTLNGK KYYFGSDSKA VTGWRIINNK
KYYFNPNNAI AAIHLCTINN DKYYFSYDGI LQNGYITIER NNFYFDANNE SKMVTGVFKG
PNGFEYFAPA NTHNNNIEGQ AIVYQNKFLT LNGKKYYFDN DSKAVTGWQT IDGKKYYFNL
NTAEAATGWQ TIDGKKYYFN LNTAEAATGW QTIDGKKYYF NTNTFIASTG YTSINGKHFY
FNTDGIMQIG VFKGPNGFEY FAPANTDANN IEGQAILYQN KFLTLNGKKY YFGSDSKAVT
GLRTIDGKKY YFNTNTAVAV TGWQTINGKK YYFNTNTSIA STGYTIISGK HFYFNTDGIM
QIGVFKGPDG FEYFAPANTD ANNIEGQAIR YQNRFLYLHD NIYYFGNNSK AATGWVTIDG
NRYYFEPNTA MGANGYKTID NKNFYFRNGL PQIGVFKGSN GFEYFAPANT DANNIEGQAI
RYQNRFLHLL GKIYYFGNNS KAVTGWQTIN GKVYYFMPDT AMAAAGGLFE IDGVIYFFGV
DGVKAPGIYG
