SP2_ANOGA
ID SP2_ANOGA Reviewed; 409 AA.
AC Q7QIJ8; Q005N3;
DT 07-APR-2021, integrated into UniProtKB/Swiss-Prot.
DT 23-OCT-2007, sequence version 4.
DT 03-AUG-2022, entry version 115.
DE RecName: Full=Serine protease inhibitor 2 {ECO:0000303|PubMed:19394412};
DE Short=Serpin 2 {ECO:0000303|PubMed:19394412};
DE Flags: Precursor;
GN Name=SRPN2 {ECO:0000303|PubMed:19394412}; Synonyms=1270169;
GN ORFNames=AgaP_AGAP006911 {ECO:0000312|EMBL:EAA04043.4};
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|Proteomes:UP000007062};
RN [1] {ECO:0000312|EMBL:ABJ52801.1}
RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RX PubMed=19394412; DOI=10.1016/j.gene.2009.04.013;
RA Suwanchaichinda C., Kanost M.R.;
RT "The serpin gene family in Anopheles gambiae.";
RL Gene 442:47-54(2009).
RN [2] {ECO:0000312|Proteomes:UP000007062}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=PEST {ECO:0000312|Proteomes:UP000007062};
RX PubMed=12364791; DOI=10.1126/science.1076181;
RA Holt R.A., Subramanian G.M., Halpern A., Sutton G.G., Charlab R.,
RA Nusskern D.R., Wincker P., Clark A.G., Ribeiro J.M.C., Wides R.,
RA Salzberg S.L., Loftus B.J., Yandell M.D., Majoros W.H., Rusch D.B., Lai Z.,
RA Kraft C.L., Abril J.F., Anthouard V., Arensburger P., Atkinson P.W.,
RA Baden H., de Berardinis V., Baldwin D., Benes V., Biedler J., Blass C.,
RA Bolanos R., Boscus D., Barnstead M., Cai S., Center A., Chaturverdi K.,
RA Christophides G.K., Chrystal M.A.M., Clamp M., Cravchik A., Curwen V.,
RA Dana A., Delcher A., Dew I., Evans C.A., Flanigan M.,
RA Grundschober-Freimoser A., Friedli L., Gu Z., Guan P., Guigo R.,
RA Hillenmeyer M.E., Hladun S.L., Hogan J.R., Hong Y.S., Hoover J.,
RA Jaillon O., Ke Z., Kodira C.D., Kokoza E., Koutsos A., Letunic I.,
RA Levitsky A.A., Liang Y., Lin J.-J., Lobo N.F., Lopez J.R., Malek J.A.,
RA McIntosh T.C., Meister S., Miller J.R., Mobarry C., Mongin E., Murphy S.D.,
RA O'Brochta D.A., Pfannkoch C., Qi R., Regier M.A., Remington K., Shao H.,
RA Sharakhova M.V., Sitter C.D., Shetty J., Smith T.J., Strong R., Sun J.,
RA Thomasova D., Ton L.Q., Topalis P., Tu Z.J., Unger M.F., Walenz B.,
RA Wang A.H., Wang J., Wang M., Wang X., Woodford K.J., Wortman J.R., Wu M.,
RA Yao A., Zdobnov E.M., Zhang H., Zhao Q., Zhao S., Zhu S.C., Zhimulev I.,
RA Coluzzi M., della Torre A., Roth C.W., Louis C., Kalush F., Mural R.J.,
RA Myers E.W., Adams M.D., Smith H.O., Broder S., Gardner M.J., Fraser C.M.,
RA Birney E., Bork P., Brey P.T., Venter J.C., Weissenbach J., Kafatos F.C.,
RA Collins F.H., Hoffman S.L.;
RT "The genome sequence of the malaria mosquito Anopheles gambiae.";
RL Science 298:129-149(2002).
RN [3] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=16113656; DOI=10.1038/sj.embor.7400478;
RA Michel K., Budd A., Pinto S., Gibson T.J., Kafatos F.C.;
RT "Anopheles gambiae SRPN2 facilitates midgut invasion by the malaria
RT parasite Plasmodium berghei.";
RL EMBO Rep. 6:891-897(2005).
RN [4] {ECO:0000305}
RP FUNCTION, INTERACTION WITH CLIPB9, SUBCELLULAR LOCATION, AND DISRUPTION
RP PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:20953892};
RX PubMed=20953892; DOI=10.1007/s00018-010-0543-z;
RA An C., Budd A., Kanost M.R., Michel K.;
RT "Characterization of a regulatory unit that controls melanization and
RT affects longevity of mosquitoes.";
RL Cell. Mol. Life Sci. 68:1929-1939(2011).
RN [5]
RP FUNCTION, INTERACTION WITH CLIPB10, AND DISRUPTION PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:33520733};
RX PubMed=33520733; DOI=10.3389/fcimb.2020.585986;
RA Zhang X., Li M., El Moussawi L., Saab S., Zhang S., Osta M.A., Michel K.;
RT "CLIPB10 is a Terminal Protease in the Regulatory Network That Controls
RT Melanization in the African Malaria Mosquito Anopheles gambiae.";
RL Front. Cell. Infect. Microbiol. 10:585986-585986(2020).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=G3 {ECO:0000269|PubMed:33045027};
RX PubMed=33045027; DOI=10.1371/journal.ppat.1008985;
RA Sousa G.L., Bishnoi R., Baxter R.H.G., Povelones M.;
RT "The CLIP-domain serine protease CLIPC9 regulates melanization downstream
RT of SPCLIP1, CLIPA8, and CLIPA28 in the malaria vector Anopheles gambiae.";
RL PLoS Pathog. 16:e1008985-e1008985(2020).
RN [7] {ECO:0007744|PDB:3PZF}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 22-409.
RX PubMed=21465556; DOI=10.1002/prot.23002;
RA An C., Lovell S., Kanost M.R., Battaile K.P., Michel K.;
RT "Crystal structure of native Anopheles gambiae serpin-2, a negative
RT regulator of melanization in mosquitoes.";
RL Proteins 79:1999-2003(2011).
RN [8] {ECO:0007744|PDB:4RO9, ECO:0007744|PDB:4ROA, ECO:0007744|PDB:4ROB, ECO:0007744|PDB:4RSQ}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 22-409 OF MUTANTS CYS-198;
RP GLU-368; TRP-358 AND CYS-359, FUNCTION, INTERACTION WITH CLIPB9,
RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF LYS-198; SER-358 AND GLU-359.
RX PubMed=25525260; DOI=10.1074/jbc.m114.625665;
RA Zhang X., Meekins D.A., An C., Zolkiewski M., Battaile K.P., Kanost M.R.,
RA Lovell S., Michel K.;
RT "Structural and inhibitory effects of hinge loop mutagenesis in serpin-2
RT from the malaria vector Anopheles gambiae.";
RL J. Biol. Chem. 290:2946-2956(2015).
CC -!- FUNCTION: Serine protease inhibitor that functions in the melanization-
CC mediated immune response (PubMed:16113656, PubMed:20953892,
CC PubMed:33520733, PubMed:33045027, PubMed:21465556, PubMed:25525260). By
CC preventing the activation of phenoloxidases through the inhibiting of
CC serine proteases CLIPB9 and CLIPB10, negatively regulates melanization
CC in the hemolymph (PubMed:16113656, PubMed:20953892, PubMed:33520733,
CC PubMed:33045027, PubMed:21465556, PubMed:25525260). By preventing
CC melanization, has a detrimental role during P.berghei parasite
CC mediated-infection and invasion of the mosquito midgut
CC (PubMed:16113656). {ECO:0000269|PubMed:16113656,
CC ECO:0000269|PubMed:20953892, ECO:0000269|PubMed:21465556,
CC ECO:0000269|PubMed:25525260, ECO:0000269|PubMed:33045027,
CC ECO:0000269|PubMed:33520733}.
CC -!- SUBUNIT: Forms a covalent heterodimer with protease CLIPB9; the
CC interaction inhibits CLIPB9 protease activity (PubMed:20953892,
CC PubMed:25525260). Forms a covalent heterodimer with protease CLIPB10;
CC the interaction inhibits CLIPB10 catalytic activity (PubMed:33520733).
CC {ECO:0000269|PubMed:20953892, ECO:0000269|PubMed:25525260,
CC ECO:0000269|PubMed:33520733}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:16113656}.
CC Note=Secreted into the hemolymph. {ECO:0000269|PubMed:16113656,
CC ECO:0000269|PubMed:20953892}.
CC -!- DEVELOPMENTAL STAGE: Expressed in embryos, larvae, pupae, and female
CC and male adults. {ECO:0000269|PubMed:19394412}.
CC -!- PTM: Protease CLIPB9 binds to SRPN2 via the hinge region resulting in
CC the cleavage of the reactive bond (PubMed:25525260). This leads to a
CC conformational change in SRPN2 which traps CLIPB9 and distorts its
CC active site, resulting in CLIPB9 inactivation (PubMed:25525260).
CC {ECO:0000269|PubMed:25525260}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown in female causes
CC spontaneous melanization leading to the formation of melanotic
CC pseudotumors and a shortening of lifespan; spontaneous melanization is
CC reduced in a SRPN2 and CLIPB9 or SRPN2 and CLIPB10 mutant backgrounds
CC (PubMed:16113656, PubMed:20953892, PubMed:33520733). During the
CC mosquito midgut infection by the rodent malaria parasite P.berghei,
CC severely reduces oocyst numbers due to an increase in ookinete lysis
CC and melanization (PubMed:16113656). Does not affect ookinete formation
CC (PubMed:16113656). Causes proteolytic cleavage of CLIPA28 and CLIPC9 in
CC absence of E.coli infection (PubMed:33045027).
CC {ECO:0000269|PubMed:16113656, ECO:0000269|PubMed:20953892,
CC ECO:0000269|PubMed:33045027, ECO:0000269|PubMed:33520733}.
CC -!- SIMILARITY: Belongs to the serpin family.
CC {ECO:0000255|RuleBase:RU000411}.
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DR EMBL; DQ974161; ABJ52801.1; -; mRNA.
DR EMBL; AAAB01008807; EAA04043.4; -; Genomic_DNA.
DR RefSeq; XP_308845.4; XM_308845.4.
DR PDB; 3PZF; X-ray; 1.75 A; A=22-409.
DR PDB; 4RO9; X-ray; 2.00 A; A/B/C=22-409.
DR PDB; 4ROA; X-ray; 1.90 A; A=22-409.
DR PDB; 4ROB; X-ray; 2.80 A; A/B/C=22-409.
DR PDB; 4RSQ; X-ray; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=22-409.
DR PDBsum; 3PZF; -.
DR PDBsum; 4RO9; -.
DR PDBsum; 4ROA; -.
DR PDBsum; 4ROB; -.
DR PDBsum; 4RSQ; -.
DR AlphaFoldDB; Q7QIJ8; -.
DR SMR; Q7QIJ8; -.
DR STRING; 7165.AGAP006911-PA; -.
DR MEROPS; I04.070; -.
DR PaxDb; Q7QIJ8; -.
DR GeneID; 1270169; -.
DR KEGG; aga:AgaP_AGAP006911; -.
DR CTD; 1270169; -.
DR VEuPathDB; VectorBase:AGAP006911; -.
DR eggNOG; KOG2392; Eukaryota.
DR HOGENOM; CLU_023330_0_1_1; -.
DR InParanoid; Q7QIJ8; -.
DR OMA; KSAQWAM; -.
DR OrthoDB; 1124079at2759; -.
DR PhylomeDB; Q7QIJ8; -.
DR Proteomes; UP000007062; Chromosome 2L.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IEA:InterPro.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0042832; P:defense response to protozoan; IDA:UniProtKB.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0035009; P:negative regulation of melanization defense response; IDA:UniProtKB.
DR GO; GO:0010955; P:negative regulation of protein processing; IMP:UniProtKB.
DR GO; GO:0045861; P:negative regulation of proteolysis; IDA:UniProtKB.
DR GO; GO:2000266; P:regulation of blood coagulation, intrinsic pathway; IEA:InterPro.
DR Gene3D; 2.30.39.10; -; 2.
DR Gene3D; 3.30.497.10; -; 1.
DR InterPro; IPR015555; AT-III.
DR InterPro; IPR023795; Serpin_CS.
DR InterPro; IPR023796; Serpin_dom.
DR InterPro; IPR000215; Serpin_fam.
DR InterPro; IPR036186; Serpin_sf.
DR InterPro; IPR042178; Serpin_sf_1.
DR InterPro; IPR042185; Serpin_sf_2.
DR PANTHER; PTHR11461; PTHR11461; 1.
DR PANTHER; PTHR11461:SF53; PTHR11461:SF53; 1.
DR Pfam; PF00079; Serpin; 1.
DR SMART; SM00093; SERPIN; 1.
DR SUPFAM; SSF56574; SSF56574; 1.
DR PROSITE; PS00284; SERPIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Glycoprotein; Immunity; Innate immunity; Protease inhibitor;
KW Reference proteome; Secreted; Serine protease inhibitor; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..409
FT /note="Serine protease inhibitor 2"
FT /evidence="ECO:0000255"
FT /id="PRO_5014588544"
FT MOTIF 356..360
FT /note="Hinge region; required for binding to peptidase"
FT /evidence="ECO:0000269|PubMed:25525260"
FT SITE 371..372
FT /note="Reactive bond"
FT /evidence="ECO:0000305|PubMed:25525260"
FT CARBOHYD 294
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 324
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT MUTAGEN 198
FT /note="K->C: 6.7-fold reduction in CLIPB9 inhibition
FT without affecting the interaction with CLIPB9; when
FT associated with C-359."
FT /evidence="ECO:0000269|PubMed:25525260"
FT MUTAGEN 358
FT /note="S->E: 3-fold increase in peptidase CLIPB9
FT inhibition. Does not affect interaction with CLIPB9."
FT /evidence="ECO:0000269|PubMed:25525260"
FT MUTAGEN 358
FT /note="S->W: Inhibits interaction with CLIPB9 but does not
FT inhibit CLIPB9 peptidase activity. Cleavage of SRNP2 by
FT CLIPB9 is not affected."
FT /evidence="ECO:0000269|PubMed:25525260"
FT MUTAGEN 359
FT /note="E->C: 6.7-fold reduction in CLIPB9 inhibition
FT without affecting the interaction with CLIPB9; when
FT associated with C-198."
FT /evidence="ECO:0000269|PubMed:25525260"
FT CONFLICT 5..7
FT /note="NFV -> SFL (in Ref. 1; ABJ52801)"
FT /evidence="ECO:0000305"
FT HELIX 36..47
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 53..55
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 57..70
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 72..74
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 81..85
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 86..89
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 95..110
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 117..127
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 134..144
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 146..151
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 156..170
FT /evidence="ECO:0007829|PDB:3PZF"
FT TURN 171..173
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 181..184
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 188..203
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 212..215
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 218..221
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 223..239
FT /evidence="ECO:0007829|PDB:3PZF"
FT TURN 240..243
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 244..251
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 254..263
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 269..275
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 278..286
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 289..298
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 300..308
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 309..314
FT /evidence="ECO:0007829|PDB:3PZF"
FT HELIX 319..321
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 322..324
FT /evidence="ECO:0007829|PDB:4RSQ"
FT TURN 328..330
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 344..353
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 355..359
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 378..381
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 386..392
FT /evidence="ECO:0007829|PDB:3PZF"
FT TURN 393..395
FT /evidence="ECO:0007829|PDB:3PZF"
FT STRAND 398..406
FT /evidence="ECO:0007829|PDB:3PZF"
SQ SEQUENCE 409 AA; 46512 MW; 37636C90AFA2D7F0 CRC64;
MNKLNFVILC LAALLVFDAT AQQDVHGPFQ GQRQNEFDLM FVKEIFKNHN SNVVLSPFSV
KILLTLIYEA SDTSFGNAVS NTKRELSSVI QNDNIDHTRS YYKQLLESAQ QDNKDYDLNI
ATNFFVDDFI EVINKYQQIA NTHYHAMLEK VSYSNPTQTA ATINNWVSEH TNGRLREIVT
PDSLEGAVIT LVNVIYFKGL WTYPFPEVAN NVKPFYGTRG KPTNAQYMEQ NGQFYYDNSA
DLGAQILRLP YRGNKLAMYF ILPNPDNTVN QVLDRINSAS LHQALWYMEE NEVNVTLPKF
KFDFSEQLNE PLQQVGIREI FSQNASLPLL ARGRGARDEV RVSRIFQKAG ITINELGSEA
YAATEIQLVN KFGGDGVQIF NANRPFIFFI EDETLGTMLF AGKIENPVF
