title: Function, mechanism and evolution of the moubatin-clade of soft tick lipocalins.
abstract: The "moubatin-clade" of soft tick lipocalins, although monophyletic, shows clear signs of paralogy as indicated by the various functions associated with this protein family. This includes anti-platelet (moubatin), anti-complement (OMCI) and toxic (TSGP2) activities in the vertebrate host. In order to understand the evolution of function and how it relates to the various paralogs in this clade, we characterized a number of different proteins in regard to undefined function and mechanism. By utilizing gain-of-function for TSGP2 and loss-of-function for TSGP3, we show that inhibition of collagen-induced platelet aggregation by moubatin and TSGP3 is due to scavenging of thromboxane A2. Moubatin, TSGP2 and TSGP3 are also able to bind leukotriene B4 with high affinity. TSGP2 and TSGP3, but not moubatin, binds complement C5, with kinetics that indicates that conformation change occurs during interaction. A conserved loop and histidine residue in the sequences of OMCI, TSGP2 and TSGP3 are implicated in the interaction with complement C5. The data presented suggest that the ancestral function evolved in this clade was aimed at inhibition of vasoconstriction, platelet aggregation and neutrophil aggregation, primarily by scavenging of thromboxane A2 and leukotriene B4. C5 complement targeting activity evolved within this clade, probably within the Old World Ornithodorinae. The moubatin-clade itself most probably derived from the related histamine and serotonin-binding lipocalin sub-family that is conserved within the Argasidae.
authors.affiliation: Laboratory for Malaria and Vector Research, National Institutes of Health, Rockville, MD 20852, USA. mansb@arc.agric.za
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Mans
authors.forename: José M C
authors.initials: JM
authors.lastname: Ribeiro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D026862:Argasidae / Q000235:genetics / Q000378:metabolism*; D060829:Arthropod Proteins; D001665:Binding Sites; D002352:Carrier Proteins; D003094:Collagen / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism; D019143:Evolution, Molecular; D066298:In Vitro Techniques; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010802:Phylogeny; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D013928:Thromboxane A2 / Q000378:metabolism
chemical_list: D060829:Arthropod Proteins; D002352:Carrier Proteins; D003182:Complement C5; D019476:Insect Proteins; D015289:Leukotrienes; D054834:Lipocalins; C521053:OmCI protein, tick; D010975:Platelet Aggregation Inhibitors; D011506:Proteins; D011994:Recombinant Proteins; C080268:moubatin; D013928:Thromboxane A2; D003094:Collagen