Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host

An Unusual Two-Domain Thyropin from Tick Saliva: NMR Solution Structure and Highly Selective Inhibition of Cysteine Cathepsins Modulated by Glycosaminoglycans

“…Protease inhibitors from tick saliva injected into the host have been shown to modulate the host immune response and suppress blood clotting at the site of tick attachment and blood feeding [47]. To date, the only studied tick salivary inhibitors of cysteine cathepsins are members of the cystatin family, which exert immunosuppressive and anti-inflammatory effects on the host [23][24][25]. A recent comparative analysis of inhibitory specificity revealed that tick salivary cystatins differ from other family members in their high affinity for endopeptidases and limited effect on exopeptidases [24].…”

“…To date, the only studied tick salivary inhibitors of cysteine cathepsins are members of the cystatin family, which exert immunosuppressive and anti-inflammatory effects on the host [23][24][25]. A recent comparative analysis of inhibitory specificity revealed that tick salivary cystatins differ from other family members in their high affinity for endopeptidases and limited effect on exopeptidases [24]. This biochemical feature makes tick salivary cystatins functionally similar to IrThy, exhibiting narrow inhibitory specificity against cysteine cathepsins with endopeptidase activities.…”

“…The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijms25042240/s1 References [6,24,68,[75][76][77][78][79] are cited in the Supplementary Materials.…”

“…Our interest in thyropins builds upon successful research into another family of protease inhibitors targeting cysteine cathepsins, the cystatins. These proteins found in tick saliva act as powerful immunomodulators of the host response, while those in the tick gut regulate blood digestion [22][23][24][25].…”