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

0580493 - BC 2024 RIV CH eng J - Článek v odborném periodiku
Martins, Larissa Almeida - Buša, Michal - Chlastáková, A. - Kotál, Jan - Beránková, Z. - Stergiou, N. - Jmel, Mohamed Amine - Schmitt, E. - Chmelař, J. - Mareš, Michael - Kotsyfakis, Michalis
Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host.
Cellular and Molecular Life Sciences. Roč. 80, č. 11 (2023), č. článku 339. ISSN 1420-682X. E-ISSN 1420-9071
Grant CEP: GA ČR(CZ) GA19-07247S; GA MŠMT(CZ) EF16_019/0000759; GA MŠMT(CZ) EF16_019/0000729; GA MŠMT(CZ) LTAUSA19109
Institucionální podpora: RVO:60077344 ; RVO:61388963
Klíčová slova: ray crystal-structure * sialostatin-l * functional expression * cysteine cathepsins * mammalian legumain * ixodes-scapularis * inhibitors * stefin * generation * peptidase * Ixodes ricinus * Tick saliva * Cystatins * Protease inhibition * Protein structure * Host-parasite interactions
Obor OECD: Biochemistry and molecular biology; Biochemistry and molecular biology (UOCHB-X)
Impakt faktor: 8, rok: 2022
Způsob publikování: Omezený přístup
https://link.springer.com/article/10.1007/s00018-023-04993-4

Tick saliva injected into the vertebrate host contains bioactive anti-proteolytic proteins from the cystatin family, however, the molecular basis of their unusual biochemical and physiological properties, distinct from those of host homologs, is unknown. Here, we present Ricistatin, a novel secreted cystatin identified in the salivary gland transcriptome of Ixodes ricinus ticks. Recombinant Ricistatin inhibited host-derived cysteine cathepsins and preferentially targeted endopeptidases, while having only limited impact on proteolysis driven by exopeptidases. Determination of the crystal structure of Ricistatin in complex with a cysteine cathepsin together with characterization of structural determinants in the Ricistatin binding site explained its restricted specificity. Furthermore, Ricistatin was potently immunosuppressive and anti-inflammatory, reducing levels of pro-inflammatory cytokines IL-6, IL-1 beta, and TNF-alpha and nitric oxide in macrophages, IL-2 and IL-9 levels in Th9 cells, and OVA antigen-induced CD4(+) T cell proliferation and neutrophil migration. This work highlights the immunotherapeutic potential of Ricistatin and, for the first time, provides structural insights into the unique narrow selectivity of tick salivary cystatins determining their bioactivity.
Trvalý link: https://hdl.handle.net/11104/0349268