Structure of Protein Having Inhibitory Disintegrin and Leukotriene Scavenging Functions Contained in Single Domain

Abstract

Background: Tablysin-15 from a blood-feeding arthropod binds integrins. Results: The structure of tablysin-15 reveals a hydrophobic channel in addition to a canonical integrin-binding RGD motif. Conclusion: Leukotrienes are ligands for the hydrophobic channel. Significance: Tablysin-15 contains an integrin-binding site and a cavity for scavenging proinflammatory leukotrienes.

The pathogen-related yeast protein Pry1, a member of the CAP protein superfamily, is a fatty acid-binding protein

“…The structure of tablysin-15 and Pry1, while displaying a similar fold, do not superimpose well with rmsd of 4.597Å for all main-atoms. The palmitate binding cavity of both proteins, however, superimpose reasonably well and reveal a conserved position and spacing of the two helices, 1 and 3, which together form the previously identified fatty acid-binding pocket (12) (Fig. 1B).…”

“…Tablysin-15 binds leukotrienes as well as free palmitic acid by a lipid-binding channel formed between the two parallel running helices, 1 and 3, and closed at the bottom by a much shorter helix 4, which runs perpendicular to helices 1 and 3 (12). To examine whether yeast Pry1 could also bind fatty acids, we first compared the sequence of tablysin-15 to that of other CAP proteins, including yeast Pry1 and Pry2.…”

“…In addition, the results indicate that sterol binding is not a universally conserved function of CAP family members, as tablysin-15 is the first CAP protein found that does not bind sterols in both the in vitro and the in vivo assay. Similarly, fatty acid-binding may not be a universally conserved feature of CAP family members, as suggested by the fact that the venom antigen Ves v 5 from wasp, does not show a hydrophobic channel in its structure (12,19).…”

“…Fatty acid binding, on the other hand, is required for the growth of yeast cells under conditions of elevated levels of intracellular free fatty acids, as occurs in mutants lacking major acyl-CoA synthetase, but is presumably also important in cells having reduced synthesis or uptake of CoA itself, or those displaying enhanced lipid remodeling induced by membrane perturbing agents. Insect venom antigens of the CAP superfamily, on the other hand, may employ this hydrophobic binding channel to scavenge and sequester immune modulators of their hosts, as exemplified by the leukotriene binding of tablysin-15 (12). The key question, of course is, what is the uniform function of the conserved CAP domain?…”

“…In addition, tablysin-15 scavenges eicosanoids as well as free fatty acids through binding these ligands in a hydrophobic channel, thereby inhibiting the proinflammatory action of cysteinyl leukotrienes that are released from mast cells in the area of the insect bite (12).…”