CDIA_ECOL5
ID CDIA_ECOL5 Reviewed; 3242 AA.
AC Q0T963;
DT 04-MAR-2015, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2006, sequence version 1.
DT 25-MAY-2022, entry version 96.
DE RecName: Full=tRNA nuclease CdiA {ECO:0000305};
DE Short=tRNase CdiA;
DE EC=3.1.-.-;
DE AltName: Full=Anticodon nuclease CdiA {ECO:0000303|PubMed:27531961};
DE AltName: Full=CdiA-EC536;
DE AltName: Full=Toxin CdiA;
DE Flags: Precursor;
GN Name=cdiA {ECO:0000303|PubMed:21085179}; OrderedLocusNames=ECP_4580;
OS Escherichia coli O6:K15:H31 (strain 536 / UPEC).
OC Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales;
OC Enterobacteriaceae; Escherichia.
OX NCBI_TaxID=362663;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=536 / UPEC;
RX PubMed=16879640; DOI=10.1111/j.1365-2958.2006.05255.x;
RA Hochhut B., Wilde C., Balling G., Middendorf B., Dobrindt U.,
RA Brzuszkiewicz E., Gottschalk G., Carniel E., Hacker J.;
RT "Role of pathogenicity island-associated integrases in the genome
RT plasticity of uropathogenic Escherichia coli strain 536.";
RL Mol. Microbiol. 61:584-595(2006).
RN [2]
RP FUNCTION, STRAIN SPECIFICITY, INTERACTION WITH CDII, SUBUNIT, AND DOMAIN.
RC STRAIN=536 / UPEC;
RX PubMed=21085179; DOI=10.1038/nature09490;
RA Aoki S.K., Diner E.J., de Roodenbeke C.T., Burgess B.R., Poole S.J.,
RA Braaten B.A., Jones A.M., Webb J.S., Hayes C.S., Cotter P.A., Low D.A.;
RT "A widespread family of polymorphic contact-dependent toxin delivery
RT systems in bacteria.";
RL Nature 468:439-442(2010).
RN [3]
RP FUNCTION, INTERACTION WITH CYSK, SUBUNIT, AND MUTAGENESIS OF HIS-3193;
RP 3239-GLY--ILE-3242 AND ILE-3242.
RC STRAIN=536 / UPEC;
RX PubMed=22333533; DOI=10.1101/gad.182345.111;
RA Diner E.J., Beck C.M., Webb J.S., Low D.A., Hayes C.S.;
RT "Identification of a target cell permissive factor required for contact-
RT dependent growth inhibition (CDI).";
RL Genes Dev. 26:515-525(2012).
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND PARTIAL DEPENDENCE ON BAMA.
RC STRAIN=536 / UPEC;
RX PubMed=23469034; DOI=10.1371/journal.pone.0057609;
RA Webb J.S., Nikolakakis K.C., Willett J.L., Aoki S.K., Hayes C.S., Low D.A.;
RT "Delivery of CdiA nuclease toxins into target cells during contact-
RT dependent growth inhibition.";
RL PLoS ONE 8:E57609-E57609(2013).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF
RP 3016-VAL--SER-3022; 3028-CYS--CYS-3034 AND HIS-3193.
RC STRAIN=536 / UPEC;
RX PubMed=24889811; DOI=10.1111/mmi.12658;
RA Beck C.M., Diner E.J., Kim J.J., Low D.A., Hayes C.S.;
RT "The F pilus mediates a novel pathway of CDI toxin import.";
RL Mol. Microbiol. 93:276-290(2014).
RN [6]
RP FUNCTION AS A TRNA NUCLEASE, REQUIRES PMF FOR TRANSLOCATION, AND
RP SUBCELLULAR LOCATION.
RC STRAIN=536 / UPEC;
RX PubMed=25174572; DOI=10.1111/mmi.12779;
RA Ruhe Z.C., Nguyen J.Y., Beck C.M., Low D.A., Hayes C.S.;
RT "The proton-motive force is required for translocation of CDI toxins across
RT the inner membrane of target bacteria.";
RL Mol. Microbiol. 94:466-481(2014).
RN [7]
RP FUNCTION, RECEPTOR FOR ENTRY INTO TARGET CELL CYTOPLASM, AND DOMAIN.
RC STRAIN=536 / UPEC;
RX PubMed=26305955; DOI=10.1073/pnas.1512124112;
RA Willett J.L., Gucinski G.C., Fatherree J.P., Low D.A., Hayes C.S.;
RT "Contact-dependent growth inhibition toxins exploit multiple independent
RT cell-entry pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:11341-11346(2015).
RN [8]
RP IDENTIFICATION OF HETEROTRIMERIC OMPC-OMPF RECEPTOR.
RC STRAIN=536 / UPEC;
RX PubMed=27723824; DOI=10.1371/journal.ppat.1005925;
RA Beck C.M., Willett J.L., Cunningham D.A., Kim J.J., Low D.A., Hayes C.S.;
RT "CdiA effectors from uropathogenic Escherichia coli use heterotrimeric
RT osmoporins as receptors to recognize target bacteria.";
RL PLoS Pathog. 12:E1005925-E1005925(2016).
RN [9]
RP DOMAIN.
RC STRAIN=536 / UPEC;
RX PubMed=28351921; DOI=10.1128/mbio.00290-17;
RA Ruhe Z.C., Nguyen J.Y., Xiong J., Koskiniemi S., Beck C.M., Perkins B.R.,
RA Low D.A., Hayes C.S.;
RT "CdiA effectors use modular receptor-binding domains to recognize target
RT bacteria.";
RL MBio 8:0-0(2017).
RN [10] {ECO:0007744|PDB:5J43, ECO:0007744|PDB:5J5V}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 3016-3242 IN COMPLEX WITH CYSK
RP AND WITH CDII AND CYSK, POSSIBLE ACTIVE SITE, COFACTOR, SUBUNIT, AND
RP MUTAGENESIS OF ASN-3164; LYS-3167; ASP-3170; TRP-3191; HIS-3193; GLU-3196;
RP THR-3200 AND ARG-3202.
RX PubMed=27531961; DOI=10.1073/pnas.1607112113;
RA Johnson P.M., Beck C.M., Morse R.P., Garza-Sanchez F., Low D.A.,
RA Hayes C.S., Goulding C.W.;
RT "Unraveling the essential role of CysK in CDI toxin activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:9792-9797(2016).
CC -!- FUNCTION: Toxic component of a toxin-immunity protein module, which
CC functions as a cellular contact-dependent growth inhibition (CDI)
CC system. CDI modules allow bacteria to communicate with and inhibit the
CC growth of closely related neighboring bacteria in a contact-dependent
CC fashion (target cell counts decrease 100- to 1000-fold). CdiA toxicity
CC is neutralized by its cognate immunity protein CdiI, but not by CdiI
CC from other bacteria (PubMed:23469034, PubMed:24889811). Uses
CC heterotrimeric OmpC and OmpF as target cell outer membrane receptors;
CC receptor function depends on polymorphisms in extracellular loops L4
CC and L5 of OmpC; interacts with itself and closely related bacteria but
CC also with OmpC from E.cloacae ATCC 13047. Its ability to preferentially
CC bind to 'self' receptors suggests it may also play a role in self-
CC recognition and kin selection (PubMed:27723824). A bamA mutation that
CC decreases its expression about 5-fold is partially resistant to this
CC strain of CdiA, probably due to decreased outer membrane receptor
CC protein assembly (PubMed:23469034). Isolated CdiA-CT is imported in an
CC F-pilus-mediated fashion; CdiA-CT inhibits F-mediated conjugation,
CC probably via its N-terminus (residues 3016-3097), although it is not
CC clear if this is physiologically significant (PubMed:24889811). Gains
CC access to the cytoplasm of target cells by using integral inner
CC membrane protein FtsH (PubMed:26305955). The C-terminal domain (CT)
CC cleaves within tRNA anticodon loops (PubMed:22333533, PubMed:24889811);
CC this activity is inhibited by cognate CdiI (PubMed:21085179,
CC PubMed:22333533, PubMed:24889811). tRNase activity of CdiA-CT is
CC stimulated by CysK, although the extreme C-terminus (residues 3098-
CC 3242) has tRNase activity in the absence of CysK. In vivo CDI toxicity
CC requires CysK (PubMed:22333533, PubMed:24889811). CysK stabilizes CdiA-
CC CT, allowing it to bind tRNA substrate; neither CdiA-CT nor CysK bind
CC tRNA alone in vitro (PubMed:27531961). Purified CdiA-CT (residues 3016-
CC 3242) inhibits E.coli cell growth when added to cultures alone or in
CC complex with cognate CdiI, growth is inhibited when cognate CdiI is
CC present within the cell but not when a CdiA-CT/CdiI complex is added
CC extracellularly, suggesting CdiA-CT alone but not the CdiA-CT/CdiI
CC complex is imported into the target cell (PubMed:24889811).
CC {ECO:0000269|PubMed:21085179, ECO:0000269|PubMed:22333533,
CC ECO:0000269|PubMed:23469034, ECO:0000269|PubMed:24889811,
CC ECO:0000269|PubMed:25174572, ECO:0000269|PubMed:26305955,
CC ECO:0000269|PubMed:27531961, ECO:0000269|PubMed:27723824}.
CC -!- FUNCTION: The CdiA protein is thought to be exported from the cell
CC through the central lumen of CdiB, the other half of its two-partner
CC system (TPS). The TPS domain probably remains associated with CdiB
CC while the FHA-1 domain forms an extended filament with the receptor-
CC binding domain (RBD) at its extremity; in the secretion arrested state
CC the C-terminus of the RBD and YP domains form a hairpin-like structure
CC as the FHA-2, PT and CT domains are periplasmic. The YP domain is
CC probably responsible for this arrest at the point where it re-enters
CC the host cell periplasm. Upon binding to a target cell outer membrane
CC receptor (heterotrimeric OmpC-OmpF for this CDI) a signal is
CC transmitted to activate secretion. The filament elongates slightly, the
CC rest of CdiA is secreted and the FHA-2 domain becomes stably associated
CC with the target cell's outer membrane where it facilitates entry of the
CC toxic CT domain into the target cell periplasm. From there the toxic CT
CC domain is cleaved and gains access to the target cell cytoplasm via an
CC inner membrane protein (FtsH for this CDI).
CC {ECO:0000305|PubMed:26305955}.
CC -!- COFACTOR:
CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
CC Evidence={ECO:0000269|PubMed:27531961};
CC Note=Mg(2+) and Ca(2+) support tRNase activity in vitro.
CC {ECO:0000269|PubMed:27531961};
CC -!- SUBUNIT: The C-terminal (CT) domain interacts with cognate CdiI but not
CC non-cognate CdiI from D.dadantii strain 3937 (PubMed:21085179). CdiA-CT
CC also interacts with CysK; this is blocked upon preincubation with O-
CC acetyl-L-serine. CysK forms a complex with CdiA-CT/CdiI
CC (PubMed:22333533). One CdiA toxin subunit binds to each subunit of the
CC CysK homodimer, and one CdiI immunity protein binds to each toxin
CC subunit; the immune complex is thus a dimer of trimers. The 4 C-
CC terminal residues of CdiA fit into the active site of CysK
CC (PubMed:27531961). {ECO:0000269|PubMed:21085179,
CC ECO:0000269|PubMed:22333533, ECO:0000269|PubMed:27531961}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23469034}. Target
CC cell membrane {ECO:0000269|PubMed:23469034}. Target cell, target cell
CC cytoplasm {ECO:0000269|PubMed:23469034, ECO:0000269|PubMed:24889811,
CC ECO:0000269|PubMed:25174572}. Note=Secreted to the cell surface by
CC CdiB, its two partner secretion pathway (TPS) partner (Probable).
CC Expressed on the cell surface of both the encoding cell, and in mixing
CC experiments on the target cell surface, in a proteinase K-sensitive
CC manner. Both the N- and C-termini can be detected on target cells,
CC whereas only the CT domain is detected in the target cell cytoplasm
CC (PubMed:23469034). Toxin translocation into the target cell depends on
CC the proton motive force of the target cell, but not on tolA or tonB
CC (PubMed:25174572). {ECO:0000269|PubMed:23469034,
CC ECO:0000269|PubMed:25174572, ECO:0000305}.
CC -!- DOMAIN: The CDI activity resides in the approximately 230 residue C-
CC terminal (CT) domain; exchanging the CT domain and cdiI gene between
CC different strains confers resistance within cognate but not non-cognate
CC systems (i.e. CdiI-536 / UPEC neutralizes CdiA-CT from strain 536 /
CC UPEC but not CdiA-CT from E.coli strain EC93, Y.pestis strain CO92 or
CC D.dadantii 3937) (PubMed:21085179). The 82 N-terminal residues (toxin
CC import domain, residues 3016-3097) are sufficient to translocate the
CC tRNA nuclease domain of colicin E5 into E.coli cells, probably via
CC binding to the F pilus (PubMed:24889811). Exchanging the outer membrane
CC receptor-binding domains between proteins exchanges the receptors
CC recognized by CdiA. Residues 1669-2310 contribute to toxin delivery
CC also (PubMed:28351921). The inner membrane translocation domain (IMTD)
CC targets the toxin to a specific target cell inner membrane protein
CC (FtsH in this case), which delivers the toxin to the target cell
CC cytoplasm. Exchanging this IMTD between CdiA proteins alters the inner
CC membrane protein delivery system but not the CdiI immunity protein,
CC strongly suggesting CdiI recognizes only the toxic domain
CC (PubMed:26305955). {ECO:0000269|PubMed:21085179,
CC ECO:0000269|PubMed:24889811, ECO:0000269|PubMed:26305955,
CC ECO:0000269|PubMed:28351921}.
CC -!- SIMILARITY: In the N-terminal section; belongs to the CdiA toxin
CC family. {ECO:0000305}.
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DR EMBL; CP000247; ABG72516.1; -; Genomic_DNA.
DR RefSeq; WP_000554175.1; NC_008253.1.
DR PDB; 5J43; X-ray; 2.70 A; B/F=3016-3242.
DR PDB; 5J5V; X-ray; 2.75 A; B/E=3016-3242.
DR PDBsum; 5J43; -.
DR PDBsum; 5J5V; -.
DR SMR; Q0T963; -.
DR STRING; 362663.ECP_4580; -.
DR EnsemblBacteria; ABG72516; ABG72516; ECP_4580.
DR KEGG; ecp:ECP_4580; -.
DR HOGENOM; CLU_000043_2_2_6; -.
DR OMA; NVADANL; -.
DR Proteomes; UP000009182; Chromosome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0030430; C:host cell cytoplasm; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0004521; F:endoribonuclease activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0000049; F:tRNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004549; F:tRNA-specific ribonuclease activity; IDA:UniProtKB.
DR Gene3D; 2.160.20.10; -; 1.
DR InterPro; IPR010069; CdiA_FHA1_rpt.
DR InterPro; IPR008638; Filamn_hemagglutn_N.
DR InterPro; IPR025157; Hemagglutinin_rpt.
DR InterPro; IPR028948; Ntox28.
DR InterPro; IPR006626; PbH1.
DR InterPro; IPR012334; Pectin_lyas_fold.
DR InterPro; IPR011050; Pectin_lyase_fold/virulence.
DR InterPro; IPR006914; VENN_dom.
DR Pfam; PF13332; Fil_haemagg_2; 4.
DR Pfam; PF05860; Haemagg_act; 1.
DR Pfam; PF15605; Ntox28; 1.
DR Pfam; PF04829; PT-VENN; 1.
DR SMART; SM00912; Haemagg_act; 1.
DR SMART; SM00710; PbH1; 7.
DR SUPFAM; SSF51126; SSF51126; 1.
DR TIGRFAMs; TIGR01901; adhes_NPXG; 1.
DR TIGRFAMs; TIGR01731; fil_hemag_20aa; 19.
PE 1: Evidence at protein level;
KW 3D-structure; Coiled coil; Endonuclease; Hydrolase; Membrane; Nuclease;
KW RNA-binding; Secreted; Signal; Target cell cytoplasm; Target cell membrane;
KW Target membrane; Toxin; tRNA-binding; Virulence.
FT SIGNAL 1..32
FT /evidence="ECO:0000305|PubMed:28351921"
FT CHAIN 33..3242
FT /note="tRNA nuclease CdiA"
FT /evidence="ECO:0000255"
FT /id="PRO_0000432088"
FT REGION 36..322
FT /note="Two-partner system transport domain (TPS)"
FT /evidence="ECO:0000305|PubMed:28351921"
FT REGION 351..1376
FT /note="FHA-1"
FT /evidence="ECO:0000305|PubMed:28351921"
FT REGION 1377..1668
FT /note="Receptor-binding domain (RBD)"
FT /evidence="ECO:0000305|PubMed:28351921"
FT REGION 1668..1852
FT /note="YP domain"
FT /evidence="ECO:0000250|UniProtKB:A0A1S4NYE3"
FT REGION 1853..1913
FT /note="Periplasmic FHA-1 repeat (pFR)"
FT /evidence="ECO:0000305|PubMed:28351921"
FT REGION 2021..2631
FT /note="FHA-2"
FT /evidence="ECO:0000305|PubMed:28351921"
FT REGION 2075..2094
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2310..2333
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2439..2481
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2969..3242
FT /note="DUF638-CT domain; not toxic when added to the
FT outside of E.coli, does not interfere with F-pilus mediated
FT conjugation, toxic when expressed intracellularly"
FT /evidence="ECO:0000269|PubMed:24889811"
FT REGION 2972..3015
FT /note="Pre-toxin (PT) domain"
FT /evidence="ECO:0000305|PubMed:28351921"
FT REGION 3016..3242
FT /note="CT domain; toxic when added to the outside of E.coli
FT and when expressed intracellularly"
FT /evidence="ECO:0000269|PubMed:22333533,
FT ECO:0000269|PubMed:24889811"
FT REGION 3016..3097
FT /note="Toxin import domain; sufficient to import the tRNA
FT nuclease domain of colicin E5 into E.coli, may bind F-pili"
FT /evidence="ECO:0000269|PubMed:24889811"
FT REGION 3020..3242
FT /note="C-terminal effector domain (CT)"
FT /evidence="ECO:0000305|PubMed:21085179"
FT REGION 3020..3141
FT /note="Inner membrane translocation domain (IMTD), targets
FT protein to FtsH"
FT /evidence="ECO:0000269|PubMed:26305955"
FT REGION 3098..3242
FT /note="tRNase function, does not interfere with F-pilus
FT mediated conjugation"
FT /evidence="ECO:0000269|PubMed:22333533,
FT ECO:0000269|PubMed:24889811"
FT REGION 3116..3146
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 3137..3238
FT /evidence="ECO:0000255"
FT MOTIF 3016..3019
FT /note="VENN CT cleavage motif"
FT /evidence="ECO:0000305"
FT ACT_SITE 3170
FT /evidence="ECO:0000305|PubMed:27531961"
FT ACT_SITE 3193
FT /evidence="ECO:0000305|PubMed:27531961"
FT ACT_SITE 3196
FT /evidence="ECO:0000305|PubMed:27531961"
FT MUTAGEN 3016..3022
FT /note="Missing: No loss of toxicity when expressed as the
FT isolated CT domain and added extracellularly to E.coli,
FT toxic when expressed intracellularly; VENN-less."
FT /evidence="ECO:0000269|PubMed:24889811"
FT MUTAGEN 3028..3034
FT /note="CAVAAPC->SAVAAPS: Not toxic when expressed as the
FT isolated CT domain and added extracellularly to E.coli,
FT does not interfere with F-pilus mediated conjugation, toxic
FT when expressed intracellularly; Cys-less. Probably has a
FT cell import defect."
FT /evidence="ECO:0000269|PubMed:24889811"
FT MUTAGEN 3164
FT /note="N->A: Wild-type growth inhibition activity in vivo."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3167
FT /note="K->A: Wild-type growth inhibition activity in vivo."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3170
FT /note="D->A: Loss of growth inhibition activity in vivo,
FT loss of tRNase activity even in presence of CysK."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3191
FT /note="W->A: Loss of growth inhibition activity in vivo,
FT significant loss of tRNase activity even in presence of
FT CysK."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3193
FT /note="H->A: Loss of tRNase activity even in the presence
FT of CysK, still binds cognate CdiI, when expressed as the
FT isolated CT domain in vitro (Ref.3), or expressed
FT intracellularly (Ref.5), or expressed as intact CdiA in
FT vivo. Protein is exported to the cell surface normally.
FT Interferes with F-pilus mediated conjugation."
FT /evidence="ECO:0000269|PubMed:22333533,
FT ECO:0000269|PubMed:24889811, ECO:0000269|PubMed:27531961"
FT MUTAGEN 3196
FT /note="E->A: Loss of growth inhibition activity in vivo,
FT loss of tRNase activity even in presence of CysK."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3200
FT /note="T->A: Wild-type growth inhibition activity in vivo."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3202
FT /note="R->A: Wild-type growth inhibition activity in vivo,
FT slight decrease in tRNase activity even in presence of
FT CysK."
FT /evidence="ECO:0000269|PubMed:27531961"
FT MUTAGEN 3239..3242
FT /note="Missing: No longer binds CysK, has no tRNase
FT activity in vitro, when expressed as the isolated CT
FT domain."
FT /evidence="ECO:0000269|PubMed:22333533"
FT MUTAGEN 3242
FT /note="Missing: No longer binds CysK in vitro, reduced
FT tRNase activity in vivo, when expressed as the isolated CT
FT domain."
FT /evidence="ECO:0000269|PubMed:22333533"
FT HELIX 3149..3164
FT /evidence="ECO:0007829|PDB:5J43"
FT STRAND 3165..3167
FT /evidence="ECO:0007829|PDB:5J43"
FT HELIX 3168..3178
FT /evidence="ECO:0007829|PDB:5J43"
FT STRAND 3183..3191
FT /evidence="ECO:0007829|PDB:5J5V"
FT HELIX 3193..3211
FT /evidence="ECO:0007829|PDB:5J43"
FT HELIX 3217..3237
FT /evidence="ECO:0007829|PDB:5J43"
FT TURN 3238..3241
FT /evidence="ECO:0007829|PDB:5J43"
SQ SEQUENCE 3242 AA; 330728 MW; 8ABA505DD6635BD8 CRC64;
MHQPPVRFTY RLLSYLISTI IAGQPLLPAV GAVITPQNGA GMDKAANGVP VVNIATPNGA
GISHNRFTDY NVGKEGLILN NATGKLNPTQ LGGLIQNNPN LKAGGEAKGI INEVTGGNRS
LLQGYTEVAG KAANVMVANP YGITCDGCGF INTPHATLTT GRPVMNADGS LQALEVTEGS
ITINGAGLDG TRSDAVSIIA RATEVNAALH AKDLTVTAGA NRITADGRVS ALKGEGDVPK
VAVDTGALGG MYARRIHLTS TESGVGVNLG NLYARDGDII LSSAGKLVLK NSLAGGNTTV
TGTDVSLSGD NKAGGNLSVT GTTGLTLNQP RLVTDKNLVL SSSGQIVQNG GELTAGQNAM
LSAQHLNQTS GTVNAAENVT LTTTNDTTLK GRSIAGKTLT VSSGSLNNGG TLVAGRDATV
KTGTFSNTGT VQGNGLKVTA TDLTSTGSIK SGSTLDISAR NATLSGDAGA KDSARVTVSG
TLENRGRLVS DDVLTLSATQ INNSGTLSGA KELVASADTL TTTEKSVTNS DGNLMLDSAS
STLAGETSAG GTVSVKGNSL KTTTTAQTQG NSVSVDVQNA QLDGTQAARD ILTLNASEKL
THSGKSSAPS LSLSAPELTS SGVLVGSALN TQSQTLTNSG LLQGEASLTV NTQRLDNQQN
GTLYSAADLT LDIPDIRNSG LITGDNGLML NAVSLSNPGK IIADTLSVRA TTLDGDGLLQ
GAGALALAGD TLSQGSHGRW LTADDLSLRG KTLNTAGTTQ GQNITVQADR WANSGSVLAT
GNLTASATGQ LTSTGDIMSQ GDTTLKAATT DNRGSLLSAG TLSLDGNSLD NSGTVQGDHV
TIRQNSVTNS GTLTGIAALT LAARMVSPQP ALMNNGGSLL TSGDLTITAG SLVNSGAIQA
ADSLTARLTG ELVSTAGSKV TSNGEMALSA LNLSNSGQWI AKNLTLKANS LTSAGDITGV
DTLTLTVNQT LNNQANGKLL SAGVLTLKAD SVTNDGQLQG NATTITAGQL TNGGHLQGET
LTLAASGGVN NRFGGVLMSR NALNVSTATL SNQGTIQGGG GVSLNVTDRL QNDSKILSGS
NLTLTAQVLA NTGSGLVQAA TLLLDVVNTV NGGRVLATGS ADVKGTTLNN TGTLQGADLL
VNYHTFSNSG TLLGTSGLGV KGSSLLQHGT GRLYSAGNLL LDAQDFSGQG QVVATGDVTL
KLIAALTNHG TLAAGKTLSV TSQNAITNGG VMQGDAMVLG AGEAFTNNGM LTAGKGNSVF
SAQRLFLNAP GSLQAGGDVS LNSRSDITIS GFTGTAGSLT MNVAGTLLNS ALIYAGNNLK
LFTDRLHNQH GDILAGNSLW VQKDASGGAN TEIINTSGNI ETHQGDIVVR TGHLLNQREG
FSATTTTRTN PSSIQGMGNA LVDIPLSLLP DGSYGYFTRE VENQHGTPCN GHGACNITMD
TLYYYAPFAD SATQRFLSSQ NITTVTGADN PAGRIASGRN LSAEAERLEN RASFILANGD
IALSGRELSN QSWQTGTENE YLVYRYDPKT FYGSYATGSL DKLPLLSPEF ENNTIRFSLD
GREKDYTPGK TYYSVIQAGG DVKTRFTSSI NNGTTTAHAG SVSPVVSAPV LNTLSQQTGG
DSLTQTALQQ YEPVVVGSPQ WHDELAGALK NIAGGSPLTG QTGISDDWPL PSGNNGYLVP
STDPDSPYLI TVNPKLDGLG QVDSHLFAGL YELLGAKPGQ APRETAPSYT DEKQFLGSSY
FLDRLGLKPE KDYRFLGDAV FDTRYVSNAV LSRTGSRYLN GLGSDTEQMR YLMDNAARQQ
KGLGLEFGVA LTAEQIAQLD GSILWWESAT INGQTVMVPK LYLSPEDITL HNGSVISGNN
VQLAGGNITN SGSSINAQNG LSLDSTGYID NLNAGLISAG GSLDLSAIGD ISNISSVISG
KTVQLESVSG NISNITRRQQ WNAGSDSRYG GVHLSGTDTG PVATIKGTDS LSLDAGKNID
ITGATVSSGG TLGMSAGNDI NIAANLISGS KSQSGFWHTD DNSASSTTSQ GSSISAGGNL
AMAAGHNLDV TASSVSAGHS ALLSAGNDLS LNAVRESKNS RNGRSESHES HAAVSTVTAG
DNLLLVAGRD VASQAAGVAA ENNVVIRGGR DVNLVAESAG AGDSYTSKKK KEINETVRQQ
GTEIASGGDT TVNAGRDITA VASSVTATGN ISVNAGRDVA LTTATESDYH YLETKKKSGG
FLSKKTTHTI SEDSASREAG SLLSGNRVTV NAGDNLTVEG SDVVADQDVS LAAGNHVDVL
AATSTDTSWR FKETKKSGLM GTGGIGFTIG SSKTTHDRRE AGTTQSQSAS TIGSTAGNVS
ITAGKQAHIS GSDVIANRDI SITGDSVVVD PGHDRRTVDE KFEQKKSGLT VALSGTVGSA
INNAVTSAQE TKESSDSRLK ALQATKTALS GVQAGQAATM ASATGDPNAT GVSLSLTTQK
SKSQQHSESD TVSGSTLNAG NNLSVVATGK NRGDNRGDIV IAGSQLKVGG NTSLDAANDI
LLSGAANTQK TTGRNSSSGG GVGVSIGAGG NGAGISVFAG VNAAKGSEKG NGTEWTETTT
DSGKTVTINS GRDTVLNGAQ VNGNRIIADV GHDLLISSQQ DTSKYDSKQT SVAAGGSFTF
GSMTGSGYIA ASRDKMKSRF DSVAEQTGMF AGDGGFDITV GRHTQLDGAV IASTATPDKN
HLDTGTLGFS DLHNEADYKV SHSGISLSGG GSFGDKFQGN MPGGMISAGG HSGHAEGTTQ
AAVAEGTITI RDRDNQKQNL ANLSRDPAHT NDSISPIFDK EKEQRRLQTV GLISDIGSQV
ADIARTQGEL NALKAAQDKY GPVPADATEE QRQAYLAKLR DTPEYKKEQE KYGTGSDMQR
GIQAATAALQ GLVGGNMAGA LAGASAPELA NIIGHHAGID DNTAAKAIAH AILGGVTAAL
QGNSAAAGAI GAGTGEVIAS AIAKSLYPGV DPSKLTEDQK QTVSTLATLS AGMAGGIASG
DVAGAAAGAG AGKNVVENNA LSLVARGCAV AAPCRTKVAE QLLEIGAKAG MAGLAGAAVK
DMADRMTSDE LEHLITLQMM GNDEITTKYL SSLHDKYGSG AASNPNIGKD LTDAEKVELG
GSGSGTGTPP PSENDPKQQN EKTVDKLNQK QESAIKKIDN TIKNALKDHD IIGTLKDMDG
KPVPKENGGY WDHMQEMQNT LRGLRNHADT LKNVNNPEAQ AAYGRATDAI NKIESALKGY
GI
