An evolutionary molecular adaptation of an unusual stefin from the liver fluke Fasciola hepatica redefines the cystatin superfamily

0570585 - ÚOCHB 2024 RIV US eng J - Journal Article
Buša, Michal - Matoušková, Zuzana - Bartošová-Sojková, Pavla - Pachl, Petr - Řezáčová, Pavlína - Eichenberger, R. M. - Deplazes, P. - Horn, Martin - Štefanić, S. - Mareš, Michael
An evolutionary molecular adaptation of an unusual stefin from the liver fluke Fasciola hepatica redefines the cystatin superfamily.
Journal of Biological Chemistry. Roč. 299, č. 3 (2023), č. článku 102970. ISSN 0021-9258. E-ISSN 1083-351X
R&D Projects: GA MŠMT(CZ) EF16_019/0000729; GA ČR(CZ) GA19-17269S; GA ČR(CZ) GA21-16565S; GA MŠMT(CZ) LTAUSA19109
Institutional support: RVO:61388963 ; RVO:60077344
Keywords : cystatin * stefin * protease inhibitor * cysteine cathepsin * protein structure * protein evolution * helminth parasite
OECD category: Biochemistry and molecular biology
Impact factor: 4.8, year: 2022
Method of publishing: Open access
https://doi.org/10.1016/j.jbc.2023.102970

Fasciolosis is a worldwide parasitic disease of ruminants and an emerging human disease caused by the liver fluke Fasciola hepatica. The cystatin superfamily of cysteine protease inhibitors is composed of distinct families of intracellular stefins and secreted true cystatins. FhCyLS-2 from F. hepatica is an unusual member of the superfamily, where our sequence and 3D structure analyses in this study revealed that it combines characteristics of both families. The protein architecture demonstrates its relationship to stefins, but FhCyLS-2 also contains the secretion signal peptide and disulfide bridges typical of true cystatins. The secretion status was confirmed by detecting the presence of FhCyLS-2 in excretory/secretory products, supported by immunolocalization. Our high-resolution crystal structure of FhCyLS-2 showed a distinct disulfide bridging pattern and functional reactive center. We determined that FhCyLS-2 is a broad specificity inhibitor of cysteine cathepsins from both the host and F. hepatica, suggesting a dual role in the regulation of exogenous and endogenous proteolysis. Based on phylogenetic analysis that identified several FhCyLS-2 homologues in liver/intestinal foodborne flukes, we propose a new group within the cystatin superfamily called cystatin-like stefins.
Permanent Link: https://hdl.handle.net/11104/0341888


Research data: RCSB PDB