TEPS3_ANOGA
ID TEPS3_ANOGA Reviewed; 1338 AA.
AC C9XI63;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 1.
DT 03-AUG-2022, entry version 50.
DE RecName: Full=Thioester-containing protein 1 allele S3 {ECO:0000303|PubMed:19797663};
DE Short=TEP1s {ECO:0000303|PubMed:15006349};
DE AltName: Full=TEP1-F {ECO:0000303|PubMed:19286136};
DE Contains:
DE RecName: Full=Thioester-containing protein 1 N-terminal {ECO:0000303|PubMed:19286136};
DE Short=TEP1-N {ECO:0000303|PubMed:19286136};
DE Contains:
DE RecName: Full=Thioester-containing protein 1 C-terminal;
DE Short=TEP1-C {ECO:0000303|PubMed:19286136};
DE Flags: Precursor;
GN Name=TEP1 {ECO:0000303|PubMed:19797663};
OS Anopheles gambiae (African malaria mosquito).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Nematocera; Culicoidea; Culicidae;
OC Anophelinae; Anopheles.
OX NCBI_TaxID=7165 {ECO:0000312|EMBL:CBA02642.1};
RN [1] {ECO:0000312|EMBL:CBA02642.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], NOMENCLATURE, AND POLYMORPHISM.
RC STRAIN=G3 {ECO:0000312|EMBL:CBA02642.1};
RX PubMed=19797663; DOI=10.1126/science.1175241;
RA Blandin S.A., Wang-Sattler R., Lamacchia M., Gagneur J., Lycett G.,
RA Ning Y., Levashina E.A., Steinmetz L.M.;
RT "Dissecting the genetic basis of resistance to malaria parasites in
RT Anopheles gambiae.";
RL Science 326:147-150(2009).
RN [2] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, POLYMORPHISM, INDUCTION, DISRUPTION
RP PHENOTYPE, AND PROTEOLYTIC CLEAVAGE.
RC STRAIN=G3 {ECO:0000269|PubMed:15006349};
RX PubMed=15006349; DOI=10.1016/s0092-8674(04)00173-4;
RA Blandin S., Shiao S.H., Moita L.F., Janse C.J., Waters A.P., Kafatos F.C.,
RA Levashina E.A.;
RT "Complement-like protein TEP1 is a determinant of vectorial capacity in the
RT malaria vector Anopheles gambiae.";
RL Cell 116:661-670(2004).
RN [3] {ECO:0000305}
RP SUBUNIT, IDENTIFICATION IN A COMPLEX WITH TEP1; LRIM1 AND APL1C,
RP SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE.
RC STRAIN=G3 {ECO:0000269|PubMed:19286136};
RX PubMed=19286136; DOI=10.1016/j.chom.2009.01.005;
RA Fraiture M., Baxter R.H., Steinert S., Chelliah Y., Frolet C.,
RA Quispe-Tintaya W., Hoffmann J.A., Blandin S.A., Levashina E.A.;
RT "Two mosquito LRR proteins function as complement control factors in the
RT TEP1-mediated killing of Plasmodium.";
RL Cell Host Microbe 5:273-284(2009).
RN [4] {ECO:0000305}
RP POLYMORPHISM.
RX PubMed=23055931; DOI=10.1371/journal.ppat.1002958;
RA Le B.V., Williams M., Logarajah S., Baxter R.H.;
RT "Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium:
RT structural analysis of TEP1 susceptible and resistant alleles.";
RL PLoS Pathog. 8:e1002958-e1002958(2012).
RN [5] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:23166497};
RX PubMed=23166497; DOI=10.1371/journal.ppat.1003029;
RA Yassine H., Kamareddine L., Osta M.A.;
RT "The mosquito melanization response is implicated in defense against the
RT entomopathogenic fungus Beauveria bassiana.";
RL PLoS Pathog. 8:e1003029-e1003029(2012).
RN [6] {ECO:0000305}
RP FUNCTION, INTERACTION WITH SPCLIP1, SUBCELLULAR LOCATION, PROTEOLYTIC
RP CLEAVAGE, AND DISRUPTION PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:24039584};
RX PubMed=24039584; DOI=10.1371/journal.ppat.1003623;
RA Povelones M., Bhagavatula L., Yassine H., Tan L.A., Upton L.M., Osta M.A.,
RA Christophides G.K.;
RT "The CLIP-domain serine protease homolog SPCLIP1 regulates complement
RT recruitment to microbial surfaces in the malaria mosquito Anopheles
RT gambiae.";
RL PLoS Pathog. 9:e1003623-e1003623(2013).
RN [7] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, AND DISRUPTION
RP PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:25012124};
RX PubMed=25012124; DOI=10.1159/000363296;
RA Yassine H., Kamareddine L., Chamat S., Christophides G.K., Osta M.A.;
RT "A serine protease homolog negatively regulates TEP1 consumption in
RT systemic infections of the malaria vector Anopheles gambiae.";
RL J. Innate Immun. 6:806-818(2014).
RN [8] {ECO:0000305}
RP POLYMORPHISM.
RX PubMed=26394016; DOI=10.1371/journal.pbio.1002255;
RA Pompon J., Levashina E.A.;
RT "A New Role of the Mosquito Complement-like Cascade in Male Fertility in
RT Anopheles gambiae.";
RL PLoS Biol. 13:e1002255-e1002255(2015).
RN [9] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:30690067};
RX PubMed=30690067; DOI=10.1016/j.ibmb.2019.01.007;
RA Yan Y., Hillyer J.F.;
RT "Complement-like proteins TEP1, TEP3 and TEP4 are positive regulators of
RT periostial hemocyte aggregation in the mosquito Anopheles gambiae.";
RL Insect Biochem. Mol. Biol. 107:1-9(2019).
CC -!- FUNCTION: Plays an essential role in the innate immune response against
CC bacteria, fungi and protozoa infection (PubMed:15006349,
CC PubMed:23166497, PubMed:24039584, PubMed:25012124, PubMed:30690067).
CC After proteolytic cleavage, the protein C-terminus binds covalently
CC through a thioester bond to the pathogen surface resulting in pathogen
CC clearance either by melanization or lysis (PubMed:24039584,
CC PubMed:30690067). Initiate the recruitment and activation of a cascade
CC of proteases, mostly of CLIP-domain serine proteases, which leads to
CC the proteolytic cleavage of the prophenoloxidase (PPO) into active
CC phenoloxidase (PO), the rate-limiting enzyme in melanin biosynthesis
CC (PubMed:24039584, PubMed:25012124, PubMed:23166497). In response to
CC parasite P.berghei-mediated infection, binds to and mediates killing of
CC ookinetes, as they egress from midgut epithelial cells into the basal
CC labyrinth, by both lysis and melanization (PubMed:15006349,
CC PubMed:25012124, PubMed:24039584). During bacterial infection, binds to
CC both Gram-positive and Gram-negative bacteria but only promotes
CC phagocytosis of Gram-negative bacteria (PubMed:24039584,
CC PubMed:30690067). Promotes the accumulation of SPCLIP1 onto the surface
CC of P.berghei ookinetes and bacterium E.coli which leads to the
CC melanization of the pathogen (PubMed:24039584). Recruits CLIPA2 to
CC bacteria surface (PubMed:25012124). In response to bacterial infection,
CC required for periostial hemocyte aggregation, but not for the
CC aggregation of sessile hemocytes in non-periostial regions
CC (PubMed:30690067). During the late stage of fungus B.bassiana-mediated
CC infection, required for the initiation of hyphae melanization by
CC binding to the surface of hyphae and recruiting prophenoloxidase PPO to
CC them (PubMed:23166497). Plays a role in male fertility by binding to
CC defective sperm cells and promoting their removal during
CC spermatogenesis (By similarity). {ECO:0000250|UniProtKB:Q9GYW4,
CC ECO:0000269|PubMed:15006349, ECO:0000269|PubMed:23166497,
CC ECO:0000269|PubMed:24039584, ECO:0000269|PubMed:25012124,
CC ECO:0000269|PubMed:30690067}.
CC -!- FUNCTION: [Thioester-containing protein 1 allele S3]: Binds to and
CC mediates killing of parasite P.bergei ookinetes by lysis.
CC {ECO:0000269|PubMed:15006349}.
CC -!- FUNCTION: [Thioester-containing protein 1 C-terminal]: Binds covalently
CC through a thioester bond to the pathogen surface resulting in pathogen
CC clearance. {ECO:0000269|PubMed:24039584, ECO:0000269|PubMed:30690067}.
CC -!- SUBUNIT: Heterodimer of a TEP1-N chain and an TEP1-C chain non-
CC covalently linked (PubMed:19286136). Forms a complex composed of TEP1-N
CC and TEP1-C heterodimer, LRIM1 and APL1C; the interaction stabilizes
CC TEP1-N and TEP1-C heterodimer, prevents its binding to tissues while
CC circulating in the hemolymph and protects the thioester bond from
CC hydrolysis (PubMed:19286136). Mature TEP1 and to a lesser extent full-
CC length TEP1 interact with SPCLIP1; the interaction is induced by
CC microbial infection (PubMed:24039584). {ECO:0000269|PubMed:19286136,
CC ECO:0000269|PubMed:24039584}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:19286136, ECO:0000269|PubMed:23166497,
CC ECO:0000269|PubMed:24039584, ECO:0000269|PubMed:25012124}.
CC Note=Secreted as a full-length protein into the hemolymph.
CC {ECO:0000269|PubMed:15006349, ECO:0000269|PubMed:19286136,
CC ECO:0000269|PubMed:23166497, ECO:0000269|PubMed:24039584,
CC ECO:0000269|PubMed:25012124}.
CC -!- INDUCTION: By parasite P.berghei infection; expression picks 24 hours
CC post infection and increases again 4 days post infection.
CC {ECO:0000269|PubMed:15006349}.
CC -!- PTM: In the hemolymph, the full-length protein is cleaved by an unknow
CC protease into a 75kDa N-terminal (TEP1-N) chain and an 80kDa C-terminal
CC (TEP1-C) chain which remain non-covalently linked (PubMed:15006349,
CC PubMed:19286136, PubMed:24039584, PubMed:25012124). The TEP1-C chain
CC contains the thioester bond which covalently binds to the pathogen
CC surface (By similarity). Cleavage is induced by bacterial infection or
CC aseptic wound injury (PubMed:24039584). During embryonic and pupal
CC development, the cleaved form is the predominant form (By similarity).
CC {ECO:0000250|UniProtKB:Q9GYW4, ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:19286136, ECO:0000269|PubMed:24039584,
CC ECO:0000269|PubMed:25012124}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q9GYW4}.
CC -!- POLYMORPHISM: TEP1 gene is highly polymorphic mainly in the region
CC surrounding the thioester bond (PubMed:19797663). After proteolytic
CC cleavage, TEP1*S alleles are more susceptible to hydrolysis of the
CC intramolecular thioester bond than TEP1*R alleles (PubMed:23055931).
CC Two main alleles have been described, TEP1*S and TEP1*R
CC (PubMed:19797663). TEP1*S1 allele (AC Q9GYW4, strain PEST) or TEP1*S3
CC allele (this entry, strain G3) confer susceptibility to parasite P.
CC berghei infection while TEP1*R1 allele (AC C9XI66, strain L3-5) confers
CC resistance to P.berghei infection (PubMed:19797663). Approximately 20%
CC of parasites survive in TEP1*S mosquitos and melanization of ookinetes
CC is less efficient (PubMed:19797663, PubMed:15006349). In TEP1*S
CC mosquitos, dead parasites are disposed by lysis, while in TEP1*R
CC mosquitoes are killed both via lysis and melanization
CC (PubMed:15006349). In TEP1*S2 male mosquitos, removal of defective
CC sperm is more efficient resulting in enhanced male fertility
CC (PubMed:26394016). {ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:19797663, ECO:0000269|PubMed:23055931,
CC ECO:0000269|PubMed:26394016}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown in females causes a 5-
CC fold increase in the number of oocysts following infection with
CC parasite P.berghei (PubMed:15006349, PubMed:25012124). Inhibits SPCLIP1
CC binding to P.berghei ookinete surface and to E.coli surface, cleavage
CC of CLIPA8 in the hemolymph and causes a severe decrease in
CC phenoloxidase (PO) activity (PubMed:24039584). In knockdown mosquitos
CC infected with bacterium E.coli, survival is reduced, bacteria
CC proliferation is increased and PO activation is severely reduced
CC (PubMed:25012124). RNAi-mediated knockdown does not affect the number
CC of periostial hemocytes in non-infected mosquitoes; however, reduces
CC the aggregation of hemocytes at the periostial regions in E.coli-
CC infected mosquitos (PubMed:30690067). No difference in the spatial
CC distribution of periostial hemocytes or sessile hemocytes outside the
CC periostial regions in absence or following E.coli infection
CC (PubMed:30690067). Slower E.coli clearance and severe reduction in
CC melanization at the periostial regions (PubMed:30690067). Increased
CC sensitivity to fungus B.bassiana (strain 80.2) infection characterized
CC by reduced mosquito survival and increased levels of hyphal body
CC colonies (PubMed:23166497). Impaired melanization of hyphae, but not of
CC germinating conidia or germ tubes, caused by a failure to recruit
CC prophenoloxidase PPO to hyphae (PubMed:23166497). Loss of phenoloxidase
CC (PO) activity triggered during late but not early fungal infection
CC (PubMed:23166497). {ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:23166497, ECO:0000269|PubMed:24039584,
CC ECO:0000269|PubMed:25012124, ECO:0000269|PubMed:30690067}.
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DR EMBL; FN431782; CBA02642.1; -; Genomic_DNA.
DR VEuPathDB; VectorBase:AGAP010815; -.
DR HOGENOM; CLU_001634_5_3_1; -.
DR OMA; YDNMGSE; -.
DR Proteomes; UP000007062; Unplaced.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0140367; P:antibacterial innate immune response; IMP:UniProtKB.
DR GO; GO:0061760; P:antifungal innate immune response; IMP:UniProtKB.
DR GO; GO:0098743; P:cell aggregation; IMP:UniProtKB.
DR GO; GO:0140546; P:defense response to symbiont; IDA:UniProtKB.
DR GO; GO:0048023; P:positive regulation of melanin biosynthetic process; IMP:UniProtKB.
DR CDD; cd02897; A2M_2; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR Gene3D; 2.60.40.690; -; 1.
DR InterPro; IPR009048; A-macroglobulin_rcpt-bd.
DR InterPro; IPR036595; A-macroglobulin_rcpt-bd_sf.
DR InterPro; IPR011625; A2M_N_BRD.
DR InterPro; IPR041813; A2M_TED.
DR InterPro; IPR011626; Alpha-macroglobulin_TED.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR001599; Macroglobln_a2.
DR InterPro; IPR019742; MacrogloblnA2_CS.
DR InterPro; IPR002890; MG2.
DR InterPro; IPR041555; MG3.
DR InterPro; IPR040839; MG4.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR Pfam; PF00207; A2M; 1.
DR Pfam; PF07703; A2M_BRD; 1.
DR Pfam; PF07677; A2M_recep; 1.
DR Pfam; PF01835; MG2; 1.
DR Pfam; PF17791; MG3; 1.
DR Pfam; PF17789; MG4; 1.
DR Pfam; PF07678; TED_complement; 1.
DR SMART; SM01360; A2M; 1.
DR SMART; SM01359; A2M_N_2; 1.
DR SMART; SM01361; A2M_recep; 1.
DR SUPFAM; SSF48239; SSF48239; 1.
DR SUPFAM; SSF49410; SSF49410; 1.
DR PROSITE; PS00477; ALPHA_2_MACROGLOBULIN; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Glycoprotein; Immunity; Reference proteome; Secreted;
KW Signal; Thioester bond.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..1338
FT /note="Thioester-containing protein 1 allele S3"
FT /evidence="ECO:0000255"
FT /id="PRO_0000455725"
FT CHAIN 22..?
FT /note="Thioester-containing protein 1 N-terminal"
FT /evidence="ECO:0000305|PubMed:15006349"
FT /id="PRO_0000455726"
FT CHAIN ?..1338
FT /note="Thioester-containing protein 1 C-terminal"
FT /evidence="ECO:0000305|PubMed:15006349"
FT /id="PRO_0000455727"
FT REGION 580..609
FT /note="May contain the cleavage site"
FT /evidence="ECO:0000250|UniProtKB:C9XI66"
FT CARBOHYD 68
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 199
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 242
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 312
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 481
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 637
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 728
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 813
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 828
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 1217..1283
FT /evidence="ECO:0000250|UniProtKB:Q9GYW4"
FT DISULFID 1326..1338
FT /evidence="ECO:0000250|UniProtKB:Q9GYW4"
FT DISULFID 1329..1334
FT /evidence="ECO:0000250|UniProtKB:Q9GYW4"
FT CROSSLNK 859..862
FT /note="Isoglutamyl cysteine thioester (Cys-Gln)"
FT /evidence="ECO:0000250|UniProtKB:Q9GYW4"
SQ SEQUENCE 1338 AA; 152039 MW; 8839E580BD8A80E8 CRC64;
MWQFIRSRIL TVIIFIGAAH GLLVVGPKFI RANQEYTLVI SNFNSQLSKV DLLLKLEGET
DNGLSVLNVT KMVDVRRNMN RMINFNMPED LTAGNYKITI DGQRGFSFHK EAELVYLSKS
ISGLIQVDKP VFKPGDTVNF RVIVLDTELK PPARVKSVHV TIRDPQRNVI RKWSTAKLYA
GVFESDLQIA PTPMLGVWNI SVEVEGEELV SKTFEVKEYV LSTFDVQVMP SVIPLEEHQA
VNLTIEANYH FGKPVQGVAK VELYLDDDKL NQKKELTVYG KGQVELRFDN FAMDADQQDV
RVKVSFIEQY TNRTVVKQSQ ITVYRYAYRV ELIKESPQFR PGLPFKCALQ FTHHDGTPAK
GITGKVEVSD VGFETTKTSD NDGLIKLELQ PSEGSEQLGI NFNAVDGFFF YEDVNKVETV
TDAYIKLELK SPIKRNKLMR FMVTCTERMT FFVYYVMSKG NIIDAGFMRP NKQTKYLLQL
NATEKMIPKA KILIATVAGR TVVYDYADLD FQELRNNFDL SIDEQEIKPG RQIELSMSGR
PGAYVGLAAY DKALLLFNKN HDLFWEDIGQ VFDGFHAINE NEFDIFHSLG LFARTLDDIL
FDSANEKTGR NALQSGKPIG KLVSYRTNFQ ESWLWKNVSI GRSGSRKLIE VVPDTTTSWY
LTGFSIDPVY GLGIIKKPIQ FTTVQPFYIV ENLPYSIKRG EAVVLQFTLF NNLGAEYIAD
VTLYNVANQT EFVGRPDTDL SYTKSVSVPP KVGVPISFLI KARKLGEMAV RVKASIMLGH
ETDALEKVIR VMPESLAQPK MDTSFFCFDD YKNQTFPFNL DINKKADNGS KKIEFRLNPN
LLTMVIKNLD NLLAVPTGCG EQNMVKFVPN ILVLDYLYAT GSKEQHLIDK ATNLLRQGYQ
NQMRYRQTDG SFGVWEKSGS SVFLTAFVAT SMQTASKYMN DIDAAMVEKA LDWLASKQHS
SGRFDETGKV WHKDMQGGLR NGVALTSYVL TALLENDIAK VKHAVVIQNG MNYLSNQLAF
INNAYDLSIA TYAMMLNGHT MKKEALDKLI DMSISDNNKK ERYWGTTNQI ETTAYALLSF
VMAEKYLDGI PIMNWLVNQR YVTGSFPRTQ DTFVGLKALT KLAEKISPSR NDYTVQLKYK
KSTKYFNINS EQIDFQNFLE IPEDTKKLEI NVGGIGFGLL EVIYQFDLNL VNFEHRFKLD
LEKQNTGSDY ELRLRVCANY IPELTDSQSN MALIEVTLPS GYVVDRNPIS EQTTVNPIQN
MEIRYGGTSV VLYYYNMGTE RNCFTVTAYR RFKVALKRPA YVVVYDYYNT NLNAIKVYEV
DKQNVCEICE EEDCPAEC
