TEPR1_ANOGA
ID TEPR1_ANOGA Reviewed; 1338 AA.
AC C9XI66;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 1.
DT 03-AUG-2022, entry version 70.
DE RecName: Full=Thioester-containing protein 1 allele R1 {ECO:0000303|PubMed:19797663};
DE Short=TEP1r {ECO:0000303|PubMed:19797663};
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 {ECO:0000303|PubMed:19286136};
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:CBA02654.1};
RN [1] {ECO:0000312|EMBL:CBA02654.1}
RP NUCLEOTIDE SEQUENCE [MRNA], NOMENCLATURE, AND POLYMORPHISM.
RC STRAIN=L3-5 {ECO:0000312|EMBL:CBA02654.1};
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=L3-5 {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 FUNCTION, SUBUNIT, IDENTIFICATION IN A COMPLEX WITH LRIM1 AND APL1C,
RP SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE.
RC STRAIN=L3-5 {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 FUNCTION, AND 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 [5] {ECO:0007744|PDB:2PN5}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 22-1338, GLYCOSYLATION AT
RP ASN-199; ASN-242; ASN-312 AND ASN-637, PROTEOLYTIC CLEAVAGE, DISULFIDE
RP BONDS, AND THIOESTER BOND.
RX PubMed=17606907; DOI=10.1073/pnas.0704967104;
RA Baxter R.H., Chang C.I., Chelliah Y., Blandin S., Levashina E.A.,
RA Deisenhofer J.;
RT "Structural basis for conserved complement factor-like function in the
RT antimalarial protein TEP1.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:11615-11620(2007).
RN [6] {ECO:0007744|PDB:4D94}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 22-1338, IDENTIFICATION IN A
RP COMPLEX WITH LRIM1 AND APL1C, SUBUNIT, PROTEOLYTIC CLEAVAGE, POLYMORPHISM,
RP GLYCOSYLATION AT ASN-199; ASN-242; ASN-312; ASN-637 AND ASN-1065, DISULFIDE
RP BONDS, THIOESTER BOND, AND MUTAGENESIS OF ASN-312 AND CYS-859.
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).
CC -!- FUNCTION: Plays an essential role in the innate immune response against
CC bacteria, fungi and protozoa infection (PubMed:15006349). After
CC proteolytic cleavage, the protein C-terminus binds covalently through a
CC thioester bond to the pathogen surface resulting in pathogen clearance
CC either by melanization or lysis (PubMed:15006349, PubMed:19286136).
CC Initiate the recruitment and activation of a cascade of proteases,
CC mostly of CLIP-domain serine proteases, which leads to the proteolytic
CC cleavage of the prophenoloxidase (PPO) into active phenoloxidase (PO),
CC the rate-limiting enzyme in melanin biosynthesis (By similarity). In
CC response to parasite P.berghei-mediated infection, binds to and
CC mediates killing of ookinetes, as they egress from midgut epithelial
CC cells into the basal labyrinth, by both lysis and melanization
CC (PubMed:15006349, PubMed:19286136). During bacterial infection, binds
CC to both Gram-positive and Gram-negative bacteria but only promotes
CC phagocytosis of Gram-negative bacteria (By similarity). Promotes the
CC accumulation of SPCLIP1 onto the surface of P.berghei ookinetes and
CC bacterium E.coli which leads to the melanization of the pathogen (By
CC similarity). Recruits CLIPA2 to bacteria surface (By similarity). In
CC response to bacterial infection, required for periostial hemocyte
CC aggregation, but not for the aggregation of sessile hemocytes in non-
CC periostial regions (By similarity). During the late stage of fungus
CC B.bassiana-mediated infection, required for the initiation of hyphae
CC melanization by binding to the surface of hyphae and recruiting
CC prophenoloxidase PPO to them (By similarity). Plays a role in male
CC fertility by binding to defective sperm cells and promoting their
CC removal during spermatogenesis (PubMed:26394016).
CC {ECO:0000250|UniProtKB:C9XI63, ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:19286136, ECO:0000269|PubMed:26394016}.
CC -!- FUNCTION: [Thioester-containing protein 1 allele R1]: Binds to and
CC mediates killing of parasite P.bergei ookinetes by lysis and
CC melanization. {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:0000250|UniProtKB:Q9GYW4}.
CC -!- SUBUNIT: Heterodimer of a TEP1-N chain and an TEP1-C chain non-
CC covalently linked (PubMed:19286136, PubMed:23055931). Forms a complex
CC composed of TEP1-N and TEP1-C heterodimer, LRIM1 and APL1C; the
CC interaction stabilizes TEP1-N and TEP1-C heterodimer, prevents its
CC binding to tissues while circulating in the hemolymph and protects the
CC thioester bond from hydrolysis (PubMed:19286136, PubMed:23055931).
CC Mature TEP1 and to a lesser extent full-length TEP1 interact with
CC SPCLIP1; the interaction is induced by microbial infection (By
CC similarity). {ECO:0000250|UniProtKB:C9XI63,
CC ECO:0000269|PubMed:19286136, ECO:0000269|PubMed:23055931}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:19286136}. Note=Secreted as a full-length protein
CC into the hemolymph. {ECO:0000269|PubMed:15006349,
CC ECO:0000269|PubMed:19286136}.
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:19286136,
CC PubMed:23055931). The TEP1-C chain contains the thioester bond which
CC covalently binds to the pathogen surface (PubMed:23055931). Cleavage is
CC induced by bacterial infection or aseptic wound injury (By similarity).
CC During embryonic and pupal development, the cleaved form is the
CC predominant form (By similarity). {ECO:0000250|UniProtKB:C9XI63,
CC ECO:0000250|UniProtKB:Q9GYW4, ECO:0000269|PubMed:19286136,
CC ECO:0000269|PubMed:23055931}.
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). Two main alleles have
CC been described, TEP1*S and TEP1*R (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 TEP1*S1 allele (AC Q9GYW4, strain PEST) or TEP1*S3 allele (AC C9XI63,
CC strain G3) confer susceptibility to parasite P. berghei infection while
CC TEP1*R1 allele (this entry, strain L3-5) confers resistance to
CC P.berghei infection (PubMed:19797663). Approximately 20% of parasites
CC survive in TEP1*S mosquitos and melanization of ookinetes is less
CC efficient (PubMed:19797663, PubMed:15006349). In TEP1*S mosquitos, dead
CC parasites are disposed by lysis, while in TEP1*R mosquitoes are killed
CC both via lysis and melanization (PubMed:15006349). In TEP1*S2 male
CC mosquitos, removal of defective sperm is more efficient resulting in
CC enhanced male fertility (PubMed:26394016).
CC {ECO:0000269|PubMed:15006349, ECO:0000269|PubMed:19797663,
CC ECO:0000269|PubMed:23055931, ECO:0000269|PubMed:26394016}.
CC -!- DISRUPTION PHENOTYPE: In RNAi-mediated knockdown females infected with
CC parasite P.berghei, causes an increase in the number of parasite
CC oocysts in the midgut and a loss of ookinete melanization.
CC {ECO:0000269|PubMed:15006349}.
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DR EMBL; FN431785; CBA02654.1; -; mRNA.
DR PDB; 2PN5; X-ray; 2.70 A; A=22-1338.
DR PDB; 4D94; X-ray; 2.70 A; A=22-1338.
DR PDBsum; 2PN5; -.
DR PDBsum; 4D94; -.
DR SMR; C9XI66; -.
DR VEuPathDB; VectorBase:AGAP010815; -.
DR HOGENOM; CLU_001634_5_3_1; -.
DR OMA; YDNMGSE; -.
DR OrthoDB; 354230at2759; -.
DR Proteomes; UP000007062; Unplaced.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0140546; P:defense response to symbiont; IDA:UniProtKB.
DR GO; GO:0048023; P:positive regulation of melanin biosynthetic process; IDA: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 3D-structure; Disulfide bond; Glycoprotein; Immunity; Reference proteome;
KW Secreted; Signal; Thioester bond.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..1338
FT /note="Thioester-containing protein 1 allele R1"
FT /evidence="ECO:0000255"
FT /id="PRO_0000455719"
FT CHAIN 22..?
FT /note="Thioester-containing protein 1 N-terminal"
FT /evidence="ECO:0000303|PubMed:19286136"
FT /id="PRO_0000455720"
FT CHAIN ?..1338
FT /note="Thioester-containing protein 1 C-terminal"
FT /evidence="ECO:0000303|PubMed:19286136"
FT /id="PRO_0000455721"
FT REGION 580..609
FT /note="May contain the cleavage site"
FT /evidence="ECO:0000269|PubMed:19286136"
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:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
FT CARBOHYD 242
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
FT CARBOHYD 312
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
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:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
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 919
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1065
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23055931,
FT ECO:0007744|PDB:4D94"
FT DISULFID 1217..1283
FT /evidence="ECO:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
FT DISULFID 1326..1338
FT /evidence="ECO:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
FT DISULFID 1329..1334
FT /evidence="ECO:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931, ECO:0007744|PDB:2PN5,
FT ECO:0007744|PDB:4D94"
FT CROSSLNK 859..862
FT /note="Isoglutamyl cysteine thioester (Cys-Gln)"
FT /evidence="ECO:0000269|PubMed:17606907,
FT ECO:0000269|PubMed:23055931"
FT MUTAGEN 312
FT /note="N->D: In absence of LRIM1/APL1C, does not affect the
FT rate of hydrolysis of the thioester bond in vitro."
FT /evidence="ECO:0000269|PubMed:23055931"
FT MUTAGEN 859
FT /note="C->A: In absence of LRIM1/APL1C, increases the rate
FT of hydrolysis of the thioester bond in vitro."
FT /evidence="ECO:0000269|PubMed:23055931"
SQ SEQUENCE 1338 AA; 151878 MW; 73DB90AE24C38B3A CRC64;
MWQFIRSRIL TVIIFIGAAH GLLVVGPKFI RANQEYTLVI SNFNSQLSKV DLLLKLEGET
DNGLSVLNVT KMVDVRRNMN RMINFNMPED LTAGNYKITI DGQRGFSFHK EAELVYLSKS
ISGLIQVDKP VFKPGDTVNF RVIVLDTELK PPARVKSVYV TIRDPQRNVI RKWSTAKLYA
GVFESDLQIA PTPMLGVWNI SVEVEGEELV SKTFEVKEYV LSTFDVQVMP SVIPLEEHQA
VNLTIEANYH FGKPVQGVAK VELYLDDDKL KLKKELTVYG KGQVELRFDN FAMDADQQDV
PVKVSFVEQY TNRTVVKQSQ ITVYRYAYRV ELIKESPQFR PGLPFKCALQ FTHHDGTPAK
GISGKVEVSD VRFETTTTSD NDGLIKLELQ PSEGTEQLSI HFNAVDGFFF YEDVNKVETV
TDAYIKLELK SPIKRNKLMR FMVTCTERMT FFVYYVMSKG NIIDAGFMRP NKQPKYLLQL
NATEKMIPRA KILIATVAGR TVVYDFADLD FQELRNNFDL SIDEQEIKPG RQIELSMSGR
PGAYVGLAAY DKALLLFNKN HDLFWEDIGQ VFDGFHAINE NEFDIFHSLG LFARTLDDIL
FDSANEKTGR NALQSGKPIG KLVSYRTNFQ ESWLWKNVSI GRSGSRKLIE VVPDTTTSWY
LTGFSIDPVY GLGIIKKPIQ FTTVQPFYIV ENLPYSIKRG EAVVLQFTLF NNLGAEYIAD
VTLYNVANQT EFVGRPNTDL SYTKSVSVPP KVGVPISFLI KARKLGEMAV RVKASIMLGH
ETDALEKVIR VMPESLVQPR MDTRFFCFDD HKNQTFPINL DINKKADSGS TKIEFRLNPN
LLTTVIKNLD HLLGVPTGCG EQNMVKFVPN ILVLDYLHAI GSKEQHLIDK ATNLLRQGYQ
NQMRYRQTDG SFGLWETTNG SVFLTAFVGT SMQTAVKYIS DIDAAMVEKA LDWLASKQHF
SGRFDKAGAE YHKEMQGGLR NGVALTSYVL MALLENDIAK AKHAEVIQKG MTYLSNQFGS
INNAYDLSIA TYAMMLNGHT MKEEALNKLI DMSFIDADKN ERFWNTTNPI ETTAYALLSF
VMAEKYTDGI PVMNWLVNQR YVTGSFPSTQ DTFVGLKALT KMAEKISPSR NDYTVQLKYK
KSAKYFKINS EQIDVENFVD IPEDTKKLEI NVGGIGFGLL EVVYQFNLNL VNFENRFQLD
LEKQNTGSDY ELRLKVCASY IPQLTDRRSN MALIEVTLPS GYVVDRNPIS EQTKVNPIQK
TEIRYGGTSV VLYYDNMGSE RNCFTLTAYR RFKVALKRPA YVVVYDYYNT NLNAIKVYEV
DKQNLCEICD EEDCPAEC
