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

Martins, Larissa Almeida; Buša, Michal; Chlastáková, A.; Kotál, Jan; Beránková, Z.; Stergiou, N.; Jmel, Mohamed Amine; Schmitt, E.; Chmelař, J.; Mareš, Michael; Kotsyfakis, Michalis

doi:https://dx.doi.org/10.1007/s00018-023-04993-4

Number of the records: 1

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

1.

SYSNO ASEP	0580493
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host
Author(s)	Martins, Larissa Almeida (BC-A)_{RID, ORCID} Buša, Michal (UOCHB-X) Chlastáková, A. (CZ) Kotál, Jan (BC-A)_{RID, ORCID} Beránková, Z. (CZ) Stergiou, N. (DE) Jmel, Mohamed Amine (BC-A)_{RID, ORCID} Schmitt, E. (DE) Chmelař, J. (CZ) Mareš, Michael (UOCHB-X)_{RID, ORCID} Kotsyfakis, Michalis (BC-A)_{RID, ORCID}
Number of authors	11
Article number	339
Source Title	Cellular and Molecular Life Sciences - ISSN 1420-682X Roč. 80, č. 11 (2023)
Number of pages	17 s.
Publication form	Online - E
Language	eng - English
Country	CH - Switzerland
Keywords	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
Subject RIV	CE - Biochemistry
OECD category	Biochemistry and molecular biology
Subject RIV - cooperation	Institute of Organic Chemistry and Biochemistry - Biochemistry
R&D Projects	GA19-07247S GA ČR - Czech Science Foundation (CSF)
	EF16_019/0000759 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	LTAUSA19109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Method of publishing	Limited access
Institutional support	BC-A - RVO:60077344 ; UOCHB-X - RVO:61388963
UT WOS	001093315500001
EID SCOPUS	85174918368
DOI	10.1007/s00018-023-04993-4
Annotation	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.
Workplace	Biology Centre (since 2006)
Contact	Dana Hypšová, eje@eje.cz, Tel.: 387 775 214
Year of Publishing	2024
Electronic address	https://link.springer.com/article/10.1007/s00018-023-04993-4

Number of the records: 1