-
Something wrong with this record ?
Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host
LA. Martins, M. Buša, A. Chlastáková, J. Kotál, Z. Beránková, N. Stergiou, MA. Jmel, E. Schmitt, J. Chmelař, M. Mareš, M. Kotsyfakis
Language English Country Switzerland
Document type Journal Article
Grant support
19-38207247S
Grantová Agentura České Republiky
NLK
PubMed Central
from 1997
ProQuest Central
from 1997-01-01 to 1 year ago
Medline Complete (EBSCOhost)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 1997-01-01 to 1 year ago
- MeSH
- Cystatins * pharmacology MeSH
- Cysteine metabolism MeSH
- Endopeptidases metabolism MeSH
- Cathepsins metabolism MeSH
- Ixodes * chemistry MeSH
- Vertebrates MeSH
- Peptide Hydrolases metabolism MeSH
- Salivary Cystatins chemistry MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
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-1β, and TNF-α 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.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc24000970
- 003
- CZ-PrNML
- 005
- 20240904095724.0
- 007
- ta
- 008
- 240109s2023 sz f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1007/s00018-023-04993-4 $2 doi
- 035 __
- $a (PubMed)37898573
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a sz
- 100 1_
- $a Martins, Larissa A $u Institute of Parasitology, Branišovská 1160/31, 37005, Ceske Budejovice, Czech Republic $u Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
- 245 10
- $a Protease-bound structure of Ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host / $c LA. Martins, M. Buša, A. Chlastáková, J. Kotál, Z. Beránková, N. Stergiou, MA. Jmel, E. Schmitt, J. Chmelař, M. Mareš, M. Kotsyfakis
- 520 9_
- $a 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-1β, and TNF-α 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.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a slinné cystatiny $x chemie $7 D055333
- 650 _2
- $a proteasy $x metabolismus $7 D010447
- 650 _2
- $a cystein $x metabolismus $7 D003545
- 650 12
- $a cystatiny $x farmakologie $7 D015891
- 650 12
- $a klíště $x chemie $7 D018884
- 650 _2
- $a obratlovci $7 D014714
- 650 _2
- $a kathepsiny $x metabolismus $7 D002403
- 650 _2
- $a endopeptidasy $x metabolismus $7 D010450
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Buša, Michal $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo N. 2, 16610, Prague, Czech Republic $7 xx0321915
- 700 1_
- $a Chlastáková, Adéla $u Department of Medical Biology, Faculty of Science, the University of South Bohemia in České Budějovice, Branišovská 1760C, 37005, Ceske Budejovice, Czech Republic
- 700 1_
- $a Kotál, Jan $u Institute of Parasitology, Branišovská 1160/31, 37005, Ceske Budejovice, Czech Republic $u Department of Medical Biology, Faculty of Science, the University of South Bohemia in České Budějovice, Branišovská 1760C, 37005, Ceske Budejovice, Czech Republic
- 700 1_
- $a Beránková, Zuzana $u Department of Medical Biology, Faculty of Science, the University of South Bohemia in České Budějovice, Branišovská 1760C, 37005, Ceske Budejovice, Czech Republic
- 700 1_
- $a Stergiou, Natascha $u Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany
- 700 1_
- $a Jmel, Mohamed Amine $u Institute of Parasitology, Branišovská 1160/31, 37005, Ceske Budejovice, Czech Republic
- 700 1_
- $a Schmitt, Edgar $u Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany
- 700 1_
- $a Chmelař, Jindřich $u Department of Medical Biology, Faculty of Science, the University of South Bohemia in České Budějovice, Branišovská 1760C, 37005, Ceske Budejovice, Czech Republic
- 700 1_
- $a Mareš, Michael $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo N. 2, 16610, Prague, Czech Republic. michael.mares@uochb.cas.cz
- 700 1_
- $a Kotsyfakis, Michail $u Institute of Parasitology, Branišovská 1160/31, 37005, Ceske Budejovice, Czech Republic. mich_kotsyfakis@yahoo.com $u Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, N. Plastira 100, 70013, Heraklion, Crete, Greece. mich_kotsyfakis@yahoo.com $1 https://orcid.org/0000000275261876
- 773 0_
- $w MED00001078 $t Cellular and molecular life sciences $x 1420-9071 $g Roč. 80, č. 11 (2023), s. 339
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/37898573 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y - $z 0
- 990 __
- $a 20240109 $b ABA008
- 991 __
- $a 20240904095720 $b ABA008
- 999 __
- $a ok $b bmc $g 2049540 $s 1210664
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2023 $b 80 $c 11 $d 339 $e 20231028 $i 1420-9071 $m Cellular and molecular life sciences $n Cell Mol Life Sci $x MED00001078
- GRA __
- $a 19-38207247S $p Grantová Agentura České Republiky
- LZP __
- $a Pubmed-20240109
