ID   EVA4_RHISA              Reviewed;         127 AA.
AC   P0C8E9;
DT   25-NOV-2008, integrated into UniProtKB/Swiss-Prot.
DT   25-NOV-2008, sequence version 1.
DT   24-JAN-2024, entry version 26.
DE   RecName: Full=Evasin-4 {ECO:0000303|PubMed:18678732, ECO:0000303|PubMed:23910450, ECO:0000303|PubMed:25266725};
DE            Short=EVA4 {ECO:0000250|UniProtKB:P0C8E8, ECO:0000305};
DE   Flags: Precursor;
OS   Rhipicephalus sanguineus (Brown dog tick) (Ixodes sanguineus).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Acari;
OC   Parasitiformes; Ixodida; Ixodoidea; Ixodidae; Rhipicephalinae;
OC   Rhipicephalus; Rhipicephalus.
OX   NCBI_TaxID=34632;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], SUBUNIT, AND FUNCTION.
RC   TISSUE=Salivary gland;
RX   PubMed=18678732; DOI=10.1084/jem.20072689;
RA   Deruaz M., Frauenschuh A., Alessandri A.L., Dias J.M., Coelho F.M.,
RA   Russo R.C., Ferreira B.R., Graham G.J., Shaw J.P., Wells T.N.C.,
RA   Teixeira M.M., Power C.A., Proudfoot A.E.I.;
RT   "Ticks produce highly selective chemokine binding proteins with
RT   antiinflammatory activity.";
RL   J. Exp. Med. 205:2019-2031(2008).
RN   [2]
RP   FUNCTION.
RX   PubMed=23910450; DOI=10.1111/febs.12463;
RA   Deruaz M., Bonvin P., Severin I.C., Johnson Z., Krohn S., Power C.A.,
RA   Proudfoot A.E.;
RT   "Evasin-4, a tick-derived chemokine-binding protein with broad selectivity
RT   can be modified for use in preclinical disease models.";
RL   FEBS J. 280:4876-4887(2013).
RN   [3]
RP   FUNCTION.
RX   PubMed=23925450; DOI=10.1160/th13-04-0297;
RA   Braunersreuther V., Montecucco F., Pelli G., Galan K., Proudfoot A.E.,
RA   Belin A., Vuilleumier N., Burger F., Lenglet S., Caffa I., Soncini D.,
RA   Nencioni A., Vallee J.P., Mach F.;
RT   "Treatment with the CC chemokine-binding protein Evasin-4 improves post-
RT   infarction myocardial injury and survival in mice.";
RL   Thromb. Haemost. 110:807-825(2013).
RN   [4]
RP   FUNCTION, AND MUTAGENESIS OF GLU-39; ASP-40; TYR-42; THR-43; THR-49;
RP   TYR-51; PHE-52; ASN-54; ASN-70; THR-74; PHE-76; GLN-95; GLN-100 AND
RP   TRP-127.
RX   PubMed=25266725; DOI=10.1074/jbc.m114.599233;
RA   Bonvin P., Dunn S.M., Rousseau F., Dyer D.P., Shaw J., Power C.A.,
RA   Handel T.M., Proudfoot A.E.;
RT   "Identification of the pharmacophore of the CC chemokine-binding proteins
RT   Evasin-1 and -4 using phage display.";
RL   J. Biol. Chem. 289:31846-31855(2014).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (1.29 ANGSTROMS) OF 24-127, DISULFIDE BONDS, SUBUNIT,
RP   NMR SPECTROSCOPY, AND RECOMBINANT EXPRESSION.
RX   PubMed=32817341; DOI=10.1074/jbc.ra120.013891;
RA   Denisov S.S., Ramirez-Escudero M., Heinzmann A.C.A., Ippel J.H.,
RA   Dawson P.E., Koenen R.R., Hackeng T.M., Janssen B.J.C., Dijkgraaf I.;
RT   "Structural characterization of anti-CCL5 activity of the tick salivary
RT   protein evasin-4.";
RL   J. Biol. Chem. 295:14367-14378(2020).
CC   -!- FUNCTION: Salivary chemokine-binding protein which has chemokine-
CC       neutralizing activity and binds to host chemokines CCL1, CCL3, CCL5,
CC       CCL7, CCL8, CCL11, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL21,
CC       CCL22, CCL23, CCL24, CCL25 and CCL26 with nanomolar affinity
CC       (PubMed:18678732, PubMed:23910450, PubMed:25266725). Binds to CCL3 and
CC       CCL5 with 1:1 stoichiometry (PubMed:23910450). Although binding to
CC       CCL25 is observed, does not inhibit CCL25-induced chemotaxis
CC       (PubMed:25266725).Has been shown to reduce cardiac injury and
CC       inflammation in mice through its anti-CCL5 activity (PubMed:23925450).
CC       {ECO:0000269|PubMed:18678732, ECO:0000269|PubMed:23910450,
CC       ECO:0000269|PubMed:23925450, ECO:0000269|PubMed:25266725}.
CC   -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:18678732,
CC       ECO:0000269|PubMed:32817341}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC   -!- DOMAIN: N-terminus residues are involved in complex formation with
CC       CCL5. A N-terminal derivative peptide composed of residues 37-54
CC       inhibits CCL5 activity in monocyte migration assays, suggesting that
CC       Evasin-4 derivatives could be used as a starting point for the
CC       development of anti-inflammatory drugs. {ECO:0000305|PubMed:32817341}.
CC   -!- SIMILARITY: Belongs to the evasin C8 family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Protein Spotlight; Note=Hidden powers - Issue 99 of
CC       November 2008;
CC       URL="https://web.expasy.org/spotlight/back_issues/099";
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DR   PDB; 6ST4; X-ray; 1.29 A; A=24-127.
DR   PDB; 6STC; X-ray; 1.69 A; A=24-127.
DR   PDB; 6STE; X-ray; 1.79 A; A/B/C/D=24-127.
DR   PDBsum; 6ST4; -.
DR   PDBsum; 6STC; -.
DR   PDBsum; 6STE; -.
DR   AlphaFoldDB; P0C8E9; -.
DR   SMR; P0C8E9; -.
DR   VEuPathDB; VectorBase:RSAN_047325; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0019957; F:C-C chemokine binding; IDA:UniProtKB.
DR   GO; GO:1900137; P:negative regulation of chemokine activity; IDA:UniProtKB.
DR   Gene3D; 2.30.130.100; -; 1.
DR   InterPro; IPR045797; EVA_Class_A.
DR   InterPro; IPR007110; Ig-like_dom.
DR   Pfam; PF19429; EVA_Class_A; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Disulfide bond; Glycoprotein; Secreted; Signal.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000255"
FT   CHAIN           24..127
FT                   /note="Evasin-4"
FT                   /evidence="ECO:0000305|PubMed:18678732"
FT                   /id="PRO_0000354059"
FT   CARBOHYD        54
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        64
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        70
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        77
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        83
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        106
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        114
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        50..69
FT                   /evidence="ECO:0000269|PubMed:32817341,
FT                   ECO:0007744|PDB:6ST4, ECO:0007744|PDB:6STC,
FT                   ECO:0007744|PDB:6STE"
FT   DISULFID        65..112
FT                   /evidence="ECO:0000269|PubMed:32817341,
FT                   ECO:0007744|PDB:6ST4, ECO:0007744|PDB:6STC,
FT                   ECO:0007744|PDB:6STE"
FT   DISULFID        86..117
FT                   /evidence="ECO:0000269|PubMed:32817341,
FT                   ECO:0007744|PDB:6ST4, ECO:0007744|PDB:6STC,
FT                   ECO:0007744|PDB:6STE"
FT   DISULFID        107..126
FT                   /evidence="ECO:0000269|PubMed:32817341,
FT                   ECO:0007744|PDB:6ST4, ECO:0007744|PDB:6STC,
FT                   ECO:0007744|PDB:6STE"
FT   MUTAGEN         39
FT                   /note="E->A: Significantly reduced binding to CCL5 and
FT                   slight reduction in inhibition of chemokine activity."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         40
FT                   /note="D->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         42
FT                   /note="Y->A: Significantly reduced binding to CCL5 and
FT                   slight reduction in inhibition of chemokine activity."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         43
FT                   /note="T->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         49
FT                   /note="T->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         51
FT                   /note="Y->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         52
FT                   /note="F->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         54
FT                   /note="N->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         70
FT                   /note="N->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         74
FT                   /note="T->A: Slightly reduced binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         76
FT                   /note="F->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         95
FT                   /note="Q->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         100
FT                   /note="Q->A: Slightly reduced binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   MUTAGEN         127
FT                   /note="W->A: No effect on binding to CCL5."
FT                   /evidence="ECO:0000269|PubMed:25266725"
FT   STRAND          46..53
FT                   /evidence="ECO:0007829|PDB:6STE"
FT   STRAND          65..70
FT                   /evidence="ECO:0007829|PDB:6ST4"
FT   STRAND          75..79
FT                   /evidence="ECO:0007829|PDB:6ST4"
FT   STRAND          85..90
FT                   /evidence="ECO:0007829|PDB:6ST4"
FT   HELIX           94..98
FT                   /evidence="ECO:0007829|PDB:6ST4"
FT   TURN            100..102
FT                   /evidence="ECO:0007829|PDB:6STC"
FT   STRAND          105..113
FT                   /evidence="ECO:0007829|PDB:6ST4"
FT   STRAND          116..126
FT                   /evidence="ECO:0007829|PDB:6ST4"
SQ   SEQUENCE   127 AA;  14126 MW;  EF315B8BFE23E602 CRC64;
     MAFKYWFVFA AVLYARQWLS TKCEVPQMTS SSAPDLEEED DYTAYAPLTC YFTNSTLGLL
     APPNCSVLCN STTTWFNETS PNNASCLLTV DFLTQDAILQ ENQPYNCSVG HCDNGTCAGP
     PRHAQCW
//