TCSL2_PAESO
ID TCSL2_PAESO Reviewed; 2364 AA.
AC P0DUB4;
DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot.
DT 07-OCT-2020, sequence version 1.
DT 03-AUG-2022, entry version 9.
DE RecName: Full=Cytotoxin-L {ECO:0000303|PubMed:24905543};
DE EC=3.4.22.- {ECO:0000250|UniProtKB:Q46342};
DE AltName: Full=Lethal toxin {ECO:0000303|PubMed:8858106};
DE Short=LT {ECO:0000303|PubMed:8858106};
DE Contains:
DE RecName: Full=Glucosyltransferase TcsL {ECO:0000305};
DE EC=2.4.1.- {ECO:0000269|PubMed:24905543, ECO:0000269|PubMed:8858106};
GN Name=tcsL {ECO:0000303|PubMed:24905543};
OS Paeniclostridium sordellii (Clostridium sordellii).
OC Bacteria; Firmicutes; Clostridia; Eubacteriales; Peptostreptococcaceae;
OC Paeniclostridium.
OX NCBI_TaxID=1505;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION (GLUCOSYLTRANSFERASE TCSL), AND
RP CATALYTIC ACTIVITY (GLUCOSYLTRANSFERASE TCSL).
RC STRAIN=VPI 9048 {ECO:0000312|EMBL:AHB59887.1};
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 [2]
RP FUNCTION (GLUCOSYLTRANSFERASE TCSL), AND CATALYTIC ACTIVITY
RP (GLUCOSYLTRANSFERASE TCSL).
RC STRAIN=VPI 9048;
RX PubMed=8858106; DOI=10.1006/bbrc.1996.1470;
RA Hofmann F., Rex G., Aktories K., Just I.;
RT "The ras-related protein Ral is monoglucosylated by Clostridium sordellii
RT lethal toxin.";
RL Biochem. Biophys. Res. Commun. 227:77-81(1996).
RN [3] {ECO:0007744|PDB:6WTS}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.3 ANGSTROMS) OF 1285-1804 IN COMPLEX
RP WITH SEMA6A, INTERACTION WITH HOST SEMA6A AND SEMA6B (CYTOTOXIN-L), AND
RP MUTAGENESIS OF 1433-CYS--GLU-1438; 1486-ALA--ILE-1497; 1505-LEU--SER-1509
RP AND 1598-ASN--ASP-1600.
RX PubMed=32589945; DOI=10.1016/j.cell.2020.06.005;
RA Lee H., Beilhartz G.L., Kucharska I., Raman S., Cui H., Lam M.H.Y.,
RA Liang H., Rubinstein J.L., Schramek D., Julien J.P., Melnyk R.A.,
RA Taipale M.;
RT "Recognition of semaphorin proteins by P. sordellii lethal toxin reveals
RT principles of receptor specificity in clostridial toxins.";
RL Cell 0:0-0(2020).
CC -!- FUNCTION: [Cytotoxin-L]: Precursor of a cytotoxin that targets the
CC vascular endothelium, inducing an anti-inflammatory effect and
CC resulting in lethal toxic shock syndrome (By similarity). TcsL
CC constitutes the main toxin that mediates the pathology of P.sordellii
CC infection, an anaerobic Gram-positive bacterium found in soil and in
CC the gastrointestinal and vaginal tracts of animals and humans; although
CC the majority of carriers are asymptomatic, pathogenic P.sordellii
CC infections arise rapidly and are highly lethal (By similarity). This
CC form constitutes the precursor of the toxin: it enters into host cells
CC and mediates autoprocessing to release the active toxin
CC (Glucosyltransferase TcsL) into the host cytosol (By similarity).
CC Targets vascular endothelium by binding to the semaphorin proteins
CC SEMA6A and SEMA6B, and enters host cells via clathrin-mediated
CC endocytosis (PubMed:32589945). Once entered into host cells,
CC acidification in the endosome promotes the membrane insertion of the
CC translocation region and formation of a pore, leading to translocation
CC of the GT44 and peptidase C80 domains across the endosomal membrane (By
CC similarity). This activates the peptidase C80 domain and autocatalytic
CC processing, releasing the N-terminal part (Glucosyltransferase TcsL),
CC which constitutes the active part of the toxin, in the cytosol (By
CC similarity). {ECO:0000250|UniProtKB:P18177,
CC ECO:0000250|UniProtKB:Q46342, ECO:0000269|PubMed:32589945}.
CC -!- FUNCTION: [Glucosyltransferase TcsL]: Active form of the toxin, which
CC is released into the host cytosol following autoprocessing and
CC inactivates small GTPases (PubMed:24905543, PubMed:8858106). Acts by
CC mediating monoglucosylation of small GTPases of the Ras (H-Ras/HRAS, K-
CC Ras/KRAS and N-Ras/NRAS) family in host cells at the conserved
CC threonine residue located in the switch I region ('Thr-37/35'), using
CC UDP-alpha-D-glucose as the sugar donor (PubMed:24905543,
CC PubMed:8858106). Does not catalyze monoglucosylation of Ral/RALA
CC (PubMed:8858106). Also able to catalyze monoglucosylation of some
CC members of the Rho family (Rac1 and Rap2A), but with less efficiency
CC than with Ras proteins (PubMed:24905543). Monoglucosylation of host
CC small GTPases completely prevents the recognition of the downstream
CC effector, blocking the GTPases in their inactive form and leading to
CC apoptosis (By similarity). Induces an anti-inflammatory effect, mainly
CC by inactivating Ras proteins which results in blockage of the cell
CC cycle and killing of immune cells (By similarity). The absence or
CC moderate local inflammatory response allows C.sordellii spreading in
CC deep tissues, production of toxin which is released in the general
CC circulation and causes a toxic shock syndrome (By similarity).
CC {ECO:0000250|UniProtKB:Q46342, ECO:0000269|PubMed:24905543,
CC ECO:0000269|PubMed:8858106}.
CC -!- CATALYTIC ACTIVITY: [Glucosyltransferase TcsL]:
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:24905543,
CC ECO:0000269|PubMed:8858106};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64685;
CC Evidence={ECO:0000269|PubMed:24905543, ECO:0000269|PubMed:8858106};
CC -!- COFACTOR: [Cytotoxin-L]:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P18177};
CC Note=Binds 1 Zn(2+) ion per subunit. Zn(2+) is required for
CC autocatalytic cleavage. {ECO:0000250|UniProtKB:P18177};
CC -!- COFACTOR: [Glucosyltransferase TcsL]:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:Q46342};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q46342};
CC Note=Has higher activity with Mn(2+), but most likely uses Mg(2+) in
CC host cells. Mn(2+) or Mg(2+) are required for glucosyltransferase
CC activity. {ECO:0000250|UniProtKB:Q46342};
CC -!- ACTIVITY REGULATION: [Cytotoxin-L]: Protease activity is activated upon
CC binding to 1D-myo-inositol hexakisphosphate (InsP6), which induces
CC conformational reorganization. {ECO:0000250|UniProtKB:Q46342}.
CC -!- SUBUNIT: [Cytotoxin-L]: Homomultimer; forms an inactive homomultimer at
CC pH 8, which dissociates at pH 4, leading to cytotoxicity (By
CC similarity). Interacts with host SEMA6A; interaction promotes toxin
CC entry into host cell (PubMed:32589945). Interacts with host SEMA6B;
CC interaction promotes toxin entry into host cell (PubMed:32589945).
CC {ECO:0000250|UniProtKB:T0D3N5, ECO:0000269|PubMed:32589945}.
CC -!- SUBCELLULAR LOCATION: [Cytotoxin-L]: Secreted
CC {ECO:0000250|UniProtKB:P18177}. Host endosome membrane
CC {ECO:0000250|UniProtKB:P18177}. Note=Secreted from P.sordellii cell
CC into the extracellular environment via help of holin-like protein
CC TcdE/UtxA. Binds to the cell surface receptors via the receptor-binding
CC region and enters the cells via clathrin-mediated endocytosis.
CC Acidification in the endosome triggers conformational changes that
CC promote the membrane insertion of the translocation region, allowing
CC formation of a pore, leading to translocation of the GT44 and peptidase
CC C80 domains across the endosomal membrane (By similarity). 1D-myo-
CC inositol hexakisphosphate-binding (InsP6) activates the peptidase C80
CC domain and autoprocessing, generating the Glucosyltransferase TcsL
CC form, which is released in the host cytosol (By similarity).
CC {ECO:0000250|UniProtKB:P18177, ECO:0000250|UniProtKB:Q46342}.
CC -!- SUBCELLULAR LOCATION: [Glucosyltransferase TcsL]: Host cytoplasm, host
CC cytosol {ECO:0000250|UniProtKB:Q46342}. 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: [Glucosyltransferase TcsL]: Consists of 4 functional domains:
CC (1) the N-terminal GT44 domain (glucosyltransferase, also named GTD),
CC which mediates glucosylation of host small GTPases, (2) an
CC autoprocessing region that catalyzes autoprocessing to release the N-
CC terminal GT44 domain in the host cytosol, (3) the translocation region
CC that forms a pore to promote translocation of the GT44 and peptidase
CC C80 domains across the endosomal membrane and (4) the receptor-binding
CC (CROPS) region that mediates binding to host cells and contribute to
CC entry into cells. {ECO:0000250|UniProtKB:Q46342}.
CC -!- DOMAIN: [Cytotoxin-L]: The receptor-binding (CROPS) region is dynamic
CC and can have open and closed conformations depending of the pH: has an
CC open conformation at endosomal pH and a closed conformation at neutral
CC pH. {ECO:0000250|UniProtKB:P18177}.
CC -!- DOMAIN: [Cytotoxin-L]: The cell wall-binding repeats bind
CC carbohydrates, probably contributing to entry into cells.
CC {ECO:0000250|UniProtKB:P16154}.
CC -!- DOMAIN: [Glucosyltransferase TcsL]: The four-helical bundle region
CC mediates binding to phospholipids, such as phosphatidylserine and
CC phosphatidic acid. This promotes localization to the inner face of the
CC cell membrane close to small GTPases. {ECO:0000250|UniProtKB:Q46342}.
CC -!- PTM: [Cytotoxin-L]: Undergoes autocatalytic cleavage to release the N-
CC terminal part (Glucosyltransferase TcsL), which constitutes the active
CC part of the toxin, in the host cytosol. 1D-myo-inositol
CC hexakisphosphate-binding (InsP6) activates the peptidase C80 domain and
CC promotes autoprocessing. {ECO:0000250|UniProtKB:Q46342}.
CC -!- SIMILARITY: Belongs to the clostridial glucosylating toxin (LCGT)
CC family. {ECO:0000305}.
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DR EMBL; KF726110; AHB59887.1; -; Genomic_DNA.
DR RefSeq; WP_021127579.1; NZ_MG205642.1.
DR PDB; 6WTS; EM; 3.30 A; C=1285-1804.
DR PDBsum; 6WTS; -.
DR AlphaFoldDB; P0DUB4; -.
DR SMR; P0DUB4; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
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; IPR020972; Dermonecrotic/RTX_toxin_MLD.
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; PF11647; MLD; 1.
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; 19.
PE 1: Evidence at protein level;
KW 3D-structure; Autocatalytic cleavage; 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..2364
FT /note="Cytotoxin-L"
FT /id="PRO_0000451199"
FT CHAIN 1..543
FT /note="Glucosyltransferase TcsL"
FT /evidence="ECO:0000250|UniProtKB:P18177"
FT /id="PRO_0000451200"
FT DOMAIN 96..468
FT /note="GT44"
FT /evidence="ECO:0000255"
FT DOMAIN 567..774
FT /note="Peptidase C80"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01107"
FT REPEAT 1833..1852
FT /note="Cell wall-binding 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 1854..1873
FT /note="Cell wall-binding 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 1876..1895
FT /note="Cell wall-binding 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 1926..1945
FT /note="Cell wall-binding 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 1946..1965
FT /note="Cell wall-binding 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 1967..1986
FT /note="Cell wall-binding 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 1987..2006
FT /note="Cell wall-binding 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2007..2026
FT /note="Cell wall-binding 8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2057..2076
FT /note="Cell wall-binding 9"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2077..2097
FT /note="Cell wall-binding 10"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2099..2118
FT /note="Cell wall-binding 11"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2119..2138
FT /note="Cell wall-binding 12"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2139..2158
FT /note="Cell wall-binding 13"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2209..2224
FT /note="Cell wall-binding 14"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2227..2249
FT /note="Cell wall-binding 15"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2250..2269
FT /note="Cell wall-binding 16"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2270..2289
FT /note="Cell wall-binding 17"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2320..2339
FT /note="Cell wall-binding 18"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REPEAT 2340..2359
FT /note="Cell wall-binding 19"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00591"
FT REGION 1..91
FT /note="Four-helical bundle"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT REGION 96..468
FT /note="Glucosyltransferase region"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT REGION 544..799
FT /note="Autoprocessing region"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT REGION 800..1500
FT /note="Translocation region"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT REGION 1433..1438
FT /note="Interaction with host SEMA6A and SEMA6B"
FT /evidence="ECO:0000269|PubMed:32589945"
FT REGION 1466..1471
FT /note="Interaction with host SEMA6A and SEMA6B"
FT /evidence="ECO:0000269|PubMed:32589945"
FT REGION 1484..1495
FT /note="Interaction with host SEMA6A and SEMA6B"
FT /evidence="ECO:0000269|PubMed:32589945"
FT REGION 1504..1511
FT /note="Interaction with host SEMA6A and SEMA6B"
FT /evidence="ECO:0000269|PubMed:32589945"
FT REGION 1596..1601
FT /note="Interaction with host SEMA6A and SEMA6B"
FT /evidence="ECO:0000269|PubMed:32589945"
FT REGION 1835..2364
FT /note="Receptor-binding (CROPS) region"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT ACT_SITE 653
FT /note="For protease activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01107"
FT ACT_SITE 698
FT /note="Nucleophile; for protease activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01107"
FT BINDING 101..103
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 139
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 265..270
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 286..288
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 288
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 515
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 518..520
FT /ligand="UDP-alpha-D-glucose"
FT /ligand_id="ChEBI:CHEBI:58885"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 518
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q46342"
FT BINDING 545
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT BINDING 546
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P18177"
FT BINDING 577
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT BINDING 600
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT BINDING 647
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT BINDING 653
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P18177"
FT BINDING 757
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P18177"
FT BINDING 764
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT BINDING 775
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT BINDING 792
FT /ligand="1D-myo-inositol hexakisphosphate"
FT /ligand_id="ChEBI:CHEBI:58130"
FT /evidence="ECO:0000250|UniProtKB:P16154"
FT SITE 543..544
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:P18177"
FT MUTAGEN 1433..1438
FT /note="CIKLIE->ELKLML: Recognizes and binds frizzled
FT receptors instead of SEMA6A and SEMA6B; when associated
FT with 1486-S--V-1497, 1505-S--Y-1509 and 1598-F--Q-1600."
FT /evidence="ECO:0000269|PubMed:32589945"
FT MUTAGEN 1486..1497
FT /note="AEFSNESIIRNI->SELSDVSLISNV: Recognizes and binds
FT frizzled receptors instead of SEMA6A and SEMA6B; when
FT associated with 1433-E--L-1438, 1505-S--Y-1509 and 1598-F--
FT Q-1600."
FT /evidence="ECO:0000269|PubMed:32589945"
FT MUTAGEN 1505..1509
FT /note="LFIYS->SFIYY: Recognizes and binds frizzled
FT receptors instead of SEMA6A and SEMA6B; when associated
FT with 1433-E--L-1438, 1486-S--V-1497 and 1598-F--Q-1600."
FT /evidence="ECO:0000269|PubMed:32589945"
FT MUTAGEN 1598..1600
FT /note="NLD->FLQ: Recognizes and binds frizzled receptors
FT instead of SEMA6A and SEMA6B; when associated with 1433-E--
FT L-1438, 1486-S--V-1497 and 1505-S--Y-1509."
FT /evidence="ECO:0000269|PubMed:32589945"
SQ SEQUENCE 2364 AA; 270302 MW; 05F7512247F36AC5 CRC64;
MSLVNKAQLQ KMAYVKFRIQ EDEYVAILNA LEEYHNMSES SVVEKYLKLK DINNLTDNYL
NTYKKSGRNK ALKKFKEYLT MEVLELKNNS LTPVEKNLHF IWIGGQINDT AINYINQWKD
VNSDYTVKVF YDSNAFLINT LKKTIVESAT NNTLESFREN LNDPEFDYNK FYRKRMEIIY
DKQKHFIDYY KSQIEENPEF IIDNIIKTYL SNEYSKDLEA LNKYIEESLN KITANNGNDI
RNLEKFADED LVRLYNQELV ERWNLAAASD ILRISMLKED GGVYLDVDML PGIQPDLFKS
INKPDSITDT SWEMIKLEAI MKYKEYIPGY TSKNFDMLDE EVQSSFESAL SSTSDKSEIF
LPLDDIKVSP LEVKIAFANN SVINQALISL KDSYGSDLVI SQIKNRYKIL NDNLNPAINE
GNDFNTTMKT FNDNLVSISN EDNIMFMIKI ADYLKVGFAP DVRSTINLSG PGVYTGAYQD
LLMFKDNSIN IHLLEPELRN FEFPKTKISQ LTEQEITSLW SFNQARAKSQ FEEYKKGYFE
GALGEDDILD FSQNTVLDKD YVVEKISSSM RTPNKEYVHY IVQLQGDNVS YEAACNLFAK
NPYYNILFQK NIENSETAYY YNLIYNKLQE IDKYRIPNLI SNRHKIKLTF IGHGKSEFNT
DTFANLDVNS LSSEIETILN LAKEDISPKS IEINLLGCNM FSYNVNVEET YPGKLLLKIK
DIVSKLMPSI SQDSITVSAN QYEVRINKEG RRELLDHSGK WINKEESIIK DISSKEYISF
NPKENKIIVK SKNLHELSTL LQEIKNNSNS SDIDLEKKVM LTECEINVAS NIDTQIVEER
IEEAKNLTSD SINYIKNEFK LIESISDALY DLKHQNGLDD SHFISFEDIS KTENGFRIRF
INKETGNSIF IETEKEIFSE YAAHISKEIS NIKDTIFDNV NGKLVKKVNL DAAHEVNTLN
SAFFIQSLIE YNTTKESLSN LSVAMKVQVY AQLFSTGLNT ITDASKVVEL VSTALDETID
LLPTLSEGLP IIATIIDGVS LGAAIKELSE TNDPLLRQEI EAKIGIMAVN LTAASTAIVT
SALGIASGFS ILLVPLAGIS AGIPSLVNNE LILQDKATKV IDYFKHISLA ETEGAFTLLD
DKIIMPQDDL VLSEIDFNNN SITLGKCEIW RTEGGSGHTF TDDIDHFFSS PSITYRKPWL
SIYDVLNIKK EKIDFSKDLM VLPNAPNRVF SYEMGWTPGF RSLDNDGTKL LDRIRDHYEG
QFYWRYFAFI ADALITKLKP RYEDTNVRIN LDGNTRSFIV PVITTEQIRK NLSYSFYGSG
GSYSLSLSPY NMNIDLNLVE NDTWVIDVDN VVKNITIESD EIQKGELIEN ILSKLNIEDN
KIVLNNHTIN FYGAINESNR FISLTFSILE DINIIIEIDL VSKSYKILLS GNCIKLIENS
SDIQQKIDHI GFNGEHQKYI PYSYIDNETK YNGFIDYSKK EGLFTAEFSN ESIIRNIYMP
DSNNLFIYSS KDLKDIRIIN KGDVKLLIGN YFKDNMKVSL SFTIEDTNTI KLNGVYLDEN
GVAQILKFMN NAKSALNTSN SLMNFLESIN IKNIFYNNLD PNIKFILDTN FIISGSNSIG
QFELICDKDK NIQPYFIKFK IKETSYTLYA GNRQNLIVEP SYHLDDSGNI SSTVINFSQK
YLYGIDRYVN KVIITPNLYT DEINITPVYK PNYICPEVII LDANYINEKI NININDLSIR
YVWDNDGSDL ILIANSEEDN QPQVKIRFVN VFKSDTAADK LSFNFSDKQD VSVSKIISTF
SLAAYSDGVF DYEFGLVSLD NECFYINSFG NMVSGLIYIN DSLYYFKPPK NNLITGFTTI
DDNKYYFDPT KSGAASIGEI TIDGKDYYFN KQGILQVGVI NTSDGLKYFA PAGTLDENLE
GESVNFIGKL NIDGKIYYFE DNYRAAVEWK SLDGETYYFN PKTGEALKGL HQIGDNKYYF
DNNGIMQTGF ITINDKVFYF NNDGVMQVGY IEVNGKYFYF GKNGERQLGV FNTPDGFKFF
GPKDDDLGTE EGELTLYNGI LNFNGKIYFF DISNTAVVGW GILDDGSTYY FDDNTAEACI
GLTVINDCKY YFDDNGIRQL GFITINDNIF YFSESGKIEL GYQNINGNYF YIDESGLVLI
GVFDTPDGYK YFAPLNTVND NIYGQAVEYS GLVRLNEDVY YFGETYKIET GWIENETDKY
YFDPETKKAY KGINVVDDIK YYFDENGIMK TGLISFENNN YYFNEDGKMQ FGYLNIKDKM
FYFGKDGKMQ IGVFNTPDGF KYFAHQNTLD ENFEGESINY TGWLDLDGKR YYFTDEYIAA
TSSLTIDGYN YYFDPDTAEL VVSE
