The following text describes a protein:
Function:
[Cytotoxin-L]: Precursor of a cytotoxin that targets the vascular endothelium, inducing an anti-inflammatory effect and resulting in lethal toxic shock syndrome. TcsL constitutes the main toxin that mediates the pathology of P.sordellii infection, an anaerobic Gram-positive bacterium found in soil and in the gastrointestinal and vaginal tracts of animals and humans; although the majority of carriers are asymptomatic, pathogenic P.sordellii infections arise rapidly and are highly lethal (By similarity). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcsL) into the host cytosol (By similarity). Targets vascular endothelium by binding to the semaphorin proteins SEMA6A and SEMA6B, and enters host cells via clathrin-mediated endocytosis (By similarity). Once entered into host cells, acidification in the endosome promotes the membrane insertion of the translocation region and formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (By similarity). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcsL), which constitutes the active part of the toxin, in the cytosol (By similarity); [Glucosyltransferase TcsL]: Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases. Acts by mediating monoglucosylation of small GTPases of the Ras (H-Ras/HRAS, K-Ras/KRAS and N-Ras/NRAS) family in host cells at the conserved threonine residue located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose as the sugar donor. Also able to catalyze monoglucosylation of some members of the Rho family (Rac1 and Rap2A), but with less efficiency than with Ras proteins. Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form and leading to apoptosis. Induces an anti-inflammatory effect, mainly by inactivating Ras proteins which results in blockage of the cell cycle and killing of immune cells. The absence or moderate local inflammatory response allows C.sordellii spreading in deep tissues, production of toxin which is released in the general circulation and causes a toxic shock syndrome.
Subcellular Localization:
[Cytotoxin-L]: Secreted. Host endosome membrane. Note=Secreted from P.sordellii cell into the extracellular environment via help of holin-like protein TcdE/UtxA. Binds to the cell surface receptors via the receptor-binding region and enters the cells via clathrin-mediated endocytosis. Acidification in the endosome triggers conformational changes that promote the membrane insertion of the translocation region, allowing formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (By similarity). 1D-myo-inositol hexakisphosphate-binding (InsP6) activates the peptidase C80 domain and autoprocessing, generating the Glucosyltransferase TcsL form, which is released in the host cytosol (By similarity); [Glucosyltransferase TcsL]: Host cytoplasm, host cytosol. Host cell membrane; Peripheral membrane protein; Cytoplasmic side. Note=Binding to phospholipids, such as phosphatidylserine and phosphatidic acid promotes localization to the inner face of the cell membrane close to its membrane anchored substrates (small GTPases).
Domain:
[Glucosyltransferase TcsL]: Consists of 4 functional domains: (1) the N-terminal GT44 domain (glucosyltransferase, also named GTD), which mediates glucosylation of host small GTPases, (2) an autoprocessing region that catalyzes autoprocessing to release the N-terminal GT44 domain in the host cytosol, (3) the translocation region that forms a pore to promote translocation of the GT44 and peptidase C80 domains across the endosomal membrane and (4) the receptor-binding (CROPS) region that mediates binding to host cells and contribute to entry into cells; [Cytotoxin-L]: The receptor-binding (CROPS) region is dynamic and can have open and closed conformations depending of the pH: has an open conformation at endosomal pH and a closed conformation at neutral pH; [Cytotoxin-L]: The cell wall-binding repeats bind carbohydrates, probably contributing to entry into cells; [Glucosyltransferase TcsL]: The four-helical bundle region mediates binding to phospholipids, such as phosphatidylserine and phosphatidic acid. This promotes localization to the inner face of the cell membrane close to small GTPases.
Sequence:
MNLVNKAQLQKMAYVKFRIQEDEYVAILNALEEYHNMSESSVVEKYLKLKDINNLTDNYLNTYKKSGRNKALKKFKEYLTMEVLELKNNSLTPVEKNLHFIWIGGQINDTAINYINQWKDVNSDYTVKVFYDSNAFLINTLKKTIVESATNNTLESFRENLNDPEFDYNKFYRKRMEIIYDKQKHFIDYYKSQIEENPEFIIDNIIKTYLSNEYSKDLEALNKYIEESLNKITANNGNDIRNLEKFADEDLVRLYNQELVERWNLAAASDILRISMLKEDGGVYLDVDMLPGIQPDLFKSINKPDSITNTSWEMIKLEAIMKYKEYIPGYTSKNFDMLDEEVQRSFESALSSKSDKSEIFLPLDDIKVSPLEVKIAFANNSVINQALISLKDSYCSDLVINQIKNRYKILNDNLNPSINEGTDFNTTMKIFSDKLASISNEDNMMFMIKITNYLKVGFAPDVRSTINLSGPGVYTGAYQDLLMFKDNSTNIHLLEPELRNFEFPKTKISQLTEQEITSLWSFNQARAKSQFEEYKKGYFEGALGEDDNLDFAQNTVLDKDYVSKKILSSMKTRNKEYIHYIVQLQGDKISYEASCNLFSKDPYSSILYQKNIEGSETAYYYSVADAEIKEIDKYRIPYQISNKRKIKLTFIGHGKSEFNTDTFANLDVDSLSSEIETILNLAKADISPKYIEINLLGCNMFSYSISAEETYPGKLLLKIKDRVSELMPSISQDSITVSANQYEVRINEEGKREILDHSGKWINKEESIIKDISSKEYISFNPKENKIIVKSKYLHELSTLLQEIRNNANSSDIDLEKKVMLTECEINVASNIDRQIVEGRIEEAKNLTSDSINYIKNEFKLIESISDSLYDLKHQNGLDDSHFISFEDISKTENGFRIRFINKETGNSIFIETEKEIFSEYATHISKEISNIKDTIFDNVNGKLVKKVNLDAAHEVNTLNSAFFIQSLIEYNTTKESLSNLSVAMKVQVYAQLFSTGLNTITDASKVVELVSTALDETIDLLPTLSEGLPIIATIIDGVSLGAAIKELSETNDPLLRQEIEAKIGIMAVNLTAASTAIVTSALGIASGFSILLVPLAGISAGIPSLVNNELILQDKATKVIDYFKHISLAETEGAFTLLDDKIIMPQDDLVLSEIDFNNNSITLGKCEIWRAEGGSGHTLTDDIDHFFSSPSITYRKPWLSIYDVLNIKKEKIDFSKDLMVLPNAPNRVFGYEMGWTPGFRSLDNDGTKLLDRIRDHYEGQFYWRYFAFIADALITKLKPRYEDTNVRINLDGNTRSFIVPVITTEQIRKNLSYSFYGSGGSYSLSLSPYNMNIDLNLVENDTWVIDVDNVVKNITIESDEIQKGELIENILSKLNIEDNKIILNNHTINFYGDINESNRFISLTFSILEDINIIIEIDLVSKSYKILLSGNCMKLIENSSDIQQKIDHIGFNGEHQKYIPYSYIDNETKYNGFIDYSKKEGLFTAEFSNESIIRNIYMPDSNNLFIYSSKDLKDIRIINKGDVKLLIGNYFKDDMKVSLSFTIEDTNTIKLNGVYLDENGVAQILKFMNNAKSALNTSNSLMNFLESINIKNIFYNNLDPNIEFILDTNFIISGSNSIGQFELICDKDKNIQPYFIKFKIKETSYTLYVGNRQNLIVEPSYHLDDSGNISSTVINFSQKYLYGIDRYVNKVIIAPNLYTDEINITPVYKPNYICPEVIILDANYINEKINVNINDLSIRYVWDNDGSDLILIANSEEDNQPQVKIRFVNVFKSDTAADKLSFNFSDKQDVSVSKIISTFSLAAYSDGFFDYEFGLVSLDNDYFYINSFGNMVSGLIYINDSLYYFKPPKNNLITGFTTIDGNKYYFDPTKSGAASIGEITIDGKDYYFNKQGILQVGVINTSDGLKYFAPAGTLDENLEGESVNFIGKLNIDGKIYYFEDNYRAAVEWKLLDDETYYFNPKTGEALKGLHQIGDNKYYFDDNGIMQTGFITINDKVFYFNNDGVMQVGYIEVNGKYFYFGKNGERQLGVFNTPDGFKFFGPKDDDLGTEEGELTLYNGILNFNGKIYFFDISNTAVVGWGTLDDGSTYYFDDNTAEACIGLTVINDCKYYFDDNGIRQLGFITINDNIFYFSESGKIELGYQNINGNYFYIDESGLVLIGVFDTPDGYKYFAPLNTVNDNIYGQAVKYSGLVRVNEDVYYFGETYKIETGWIENETDKYYFDPETKKAYKGINVVDDIKYYFDENGIMRTGLISFENNNYYFNEDGKMQFGYLNIKDKMFYFGKDGKMQIGVFNTPDGFKYFAHQNTLDENFEGESINYTGWLDLDGKRYYFTDEYIAATGSLTIDGYNYYFDPDTAELVVSE